Meningitis StreptococcalPhase 2NCT03112031
Treatment With Tamoxifen in Cryptococcal Meningitis
A Phase 2 study testing Tamoxifen, Amphotericin B and Fluconazole in people with Meningitis Streptococcal and Hiv, run by Oxford University Clinical Research Unit, Vietnam at 3 sites in Vietnam.
Trial summary
The purpose of this study is to develop initial efficacy, feasibility, and safety data regarding the use of Tamoxifen in combination with amphotericin B and fluconazole in the treatment of cryptococcal meningitis. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Meningitis Streptococcal, Hiv, Meningitis
- What is being tested?
- Tamoxifen, Amphotericin B and Fluconazole
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 3 sitesVietnam
- Study dates
- 10 Oct 2017to 17 Jul 2018
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Cryptococcal meningitis (CM) defined as a syndrome consistent with CM and one or more of:
- positive CSF India ink (budding encapsulated yeasts),
- C. neoformans cultured from CSF or blood,
- positive cryptococcal antigen Lateral Flow Antigen Test (LFA) in CSF
- Informed consent to participate given by patient or acceptable representative
- Known HIV infection status, or patient agrees to HIV testing on this admission
Who cannot join
- Pregnancy or breast-feeding
- History of thromboembolic disease such as pulmonary embolism or deep venous thrombosis
- On anti-coagulant medication
- On medication known to prolong the QT interval other than fluconazole, such as fluoroquinolones or antidepressants.
- Known cardiac conduction defect including long QT syndromes
- QTc at baseline > 500ms
Show all 13Show fewer
- Currently receiving treatment for cryptococcal meningitis and having received > 4 days of anti-cryptococcal meningitis therapy
- Known allergy to Tamoxifen
- Currently or history of receiving treatment with Tamoxifen for breast cancer or other indication
- Current or history of uterine cancer including endometrial cancer and uterine sarcoma
- Renal failure (defined as creatinine >3*ULN (upper limit of normal), despite adequate hydration)
- Failure to consent - the patient, or if they are incapacitated, their responsible relative, declines to enter the study
- Allergy to amphotericin B or fluconazole
Trial locations and contacts
3 sites in 1 country.
Vietnam3 sites
Cho Ray Hospital
Ho Chi Minh City
Hospital for Tropical Diseases
Ho Chi Minh City
Oxford University Clinical Research Unit
Ho Chi Minh City
About this study
Official title: A Randomized Trial of Tamoxifen Combined With Amphotericin B and Fluconazole for Cryptococcal Meningitis
The purpose of this study is to develop initial efficacy, feasibility, and safety data regarding the use of Tamoxifen in combination with amphotericin B and fluconazole in the treatment of cryptococcal meningitis. The results of the study will inform the design and feasibility of a larger study powered to a survival endpoint. The study hypothesis is that adding tamoxifen to standard antifungal therapy increases the rate of clearance of yeast from cerebrospinal fluid. Increased rates of clearance of yeast from cerebrospinal fluid have previously been associated with improved clinical outcomes, including survival and disability.
Read the detailed description
A randomized, open-label trial with 2 parallel arms: standard antifungal therapy versus tamoxifen augmented antifungal therapy during the first 2 weeks (induction phase) of treatment. The study will recruit in two sites in Ho Chi Minh City: the Hospital for Tropical Diseases (HTD), and Cho Ray Hospital (CRH). 25 patients will be enrolled into the two study arms (intervention versus control). All anti-fungal administration will be directly observed by ward staff.
Intervention arm: Induction phase treatment (days 1-14): Tamoxifen will be given orally in a dose of 300mg/day for the first 14 days following randomization. It will be administered by nasogastric tube where patients are unconscious. In addition patients will receive amphotericin 1mg/kg once daily iv and fluconazole 800mg once daily orally. The tamoxifen will be administered in the morning combined with amphotericin and fluconazole dose.
Control arm: Induction phase treatment (days 1-14): Patients will receive amphotericin 1mg/kg/day combined with fluconazole 800mg once daily for the first 2 weeks. Amphotericin and fluconazole will be administered simultaneously.
The primary efficacy endpoint will be the rate of clearance of yeast cells from cerebrospinal fluid (CSF) over the first 2 weeks following randomisation. Patients will be followed for 10 weeks, which is conventional in clinical trials in cryptococcal meningitis. After the first 2 weeks of study treatment, all patients will receive fluconazole 800mg/day for 8 further weeks, until the study end. At this point, HIV infected patients will be switched to long term secondary prophylaxis with fluconazole 200mg/day as per standard practice. For HIV uninfected patients, the decision to continue antifungal treatment, and at which dose, will be made on a case by case basis by the attending physician in consultation with the patient.
- Conditions
- Meningitis Streptococcal, Hiv, Meningitis, Meningoencephalitis
- Being tested
- Tamoxifen, Amphotericin B, Fluconazole
- Keywords
- Tamoxifen, Cryptococcal meningitis, Cryptococcus neoformans, Human immunodeficiency virus
- Medical subject headings
- Acquired Immunodeficiency Syndrome, Meningitis, Meningoencephalitis, Meningitis, Cryptococcal, Cryptococcosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TamoxifenDrug
Also called Nolvadex - D
Tamoxifen will be given orally in a dose of 300mg/day for the first 14 days following randomization. It will be administered by nasogastric tube where patients are unconscious. The Tamoxifen will be administered in the morning combined with amphotericin and fluconazole dose.
Amphotericin BDrug
Also called Amphotret
Patients will receive amphotericin 1mg/kg/day i.v. once daily orally for the first 2 weeks.
FluconazoleDrug
Also called Zolmed 200
Patients will receive fluconazole 800mg once daily orally for the first 2 weeks. Amphotericin and fluconazole will be administered simultaneously. After the first 2 weeks of study treatment, all patients will receive fluconazole 800mg/day for 8 further weeks, until the study end.
| Study group | Role | What they receive |
|---|---|---|
| Tamoxifen augmented antifungal therapy | Experimental | Tamoxifen 300mg/day for 2 weeks, combined with standard antifungal therapy (amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks) Receives: Drug: Tamoxifen; Drug: Amphotericin B; Drug: Fluconazole |
| Standard antifungal therapy | Active comparator | Amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks. Receives: Drug: Amphotericin B; Drug: Fluconazole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Early Fungicidal Activity (EFA), i.e. the rate of clearance of yeast from cerebrospinal fluid
In the trial, lumbar punctures are scheduled on days 1, 3, 7, 14, and additionally as clinically indicated. Whenever a lumbar puncture is performed, the study team will determine the amount of viable yeast in CSF through culture. Based on the patients' longitudinal quantitative yeast count measurements, EFA will be determined as previously described e.g. see N Engl J Med 2016; 374:542-54
Measured: over the first 2 weeks following randomisation
Secondary outcomes (11)
Survival until 10 weeks after randomization
International treatment guidelines recommend 10 weeks of high dose antifungal therapy for cryptococcal meningitis - an initial phase of amphotericin based induction therapy for 2 weeks followed by 8 weeks of moderate to high dose fluconazole. The rate of survival until this 10 week period of therapy is completed is a frequent endpoint in trials of treatment for cryptococcal meningitis.
Measured: 10 weeks after randomisation
Disability at 10 weeks
Disability is an expected consequence of cryptococcal meningitis, including blindness, deafness and other focal neurological deficits. Neurological disability will be assessed using the modified Rankin score and the Two Simple Questions, and the results of each test combined and classified as good, intermediate, severe disability, or death, as we have previously published.
Measured: at 10 weeks
Adverse events
The proportion of patients with any grade 3 or 4 adverse event, serious adverse event, or unexpected serious adverse event will be compared between treatment groups.
Measured: During hospital stay, an average of 10 weeks
Rate of IRIS until 10 weeks (in HIV infected patients only)
The investigators will model the rate of IRIS over time with a cause-specific hazards model taking into account the competing risk of prior death.
Measured: until 10 weeks
Rate of Cryptococcal meningitis relapse
A pragmatic definition of relapse will be used. This is defined as either intensification of antifungal therapy above that according to the study antifungal schedule, or readmission for treatment of cryptococcal disease.
Measured: until 10 weeks
QT prolongation
Prolongation of the QT interval is a potential side-effect of both Tamoxifen and fluconazole, although it is not clear that either drug increases the risk of Torsade de Pointes, a potentially life-threatening arrhythmia. The QT interval will be estimated manually from 3 chest and 3 limb leads from a high resolution (50mm/sec) 12-lead ECG. The median value will be determined and used to calculate the corrected QT interval (QTc) using using Framingham's formula
Measured: During hospital stay, an average of 10 weeks
Visual deficit at 10 weeks
Visual deficit occurs in 5-40% of patients with cryptococcal meningitis depending upon underlying immune status. The pathogenesis is unclear. The study team will compare the incidence of blindness and other visual deficit between treatment groups. Visual deficit will be assessed using a simple 6 point scale.
Measured: at 10 weeks
Time to new neurological event or death until 10 weeks
A neurological event is defined as a fall in Glasgow coma score by ≥2 points for ≥2 days from the highest previously recorded Glasgow coma score (including baseline) or the occurrence of any of the following adverse events: cerebellar symptoms, coma, hemiplegia, paraplegia, seizures, cerebral herniation, new onset blindness or deafness, or cranial nerve palsy.
Measured: until 10 weeks
Longitudinal measurements of intracranial pressure during the first 2 weeks
Intracranial pressure (ICP) will be measured at study entry, day 3, 7, and 14, and at other times as clinically indicated. The decline in raised intracranial pressure over the first 2 weeks will be modelled and compared between treatment arms.
Measured: during the first 2 weeks
CD4 count at 10 weeks
CD4 count measurement is indicated in HIV infected patients, and CD4 lymphopenia has been described in HIV uninfected patients with cryptococcal meningitis. Moreover, Tamoxifen may reduce CD4 cell apoptosis which may be beneficial.
Measured: at 10 weeks
Blood and CSF concentrations of amphotericin, Tamoxifen and fluconazole
All patients will undergo pharmacokinetic sampling to enable the description of the concentrations of Tamoxifen and fluconazole in plasma and CSF, and of amphotericin in blood, and relate these to the rate of clearance of yeast from CSF.
Measured: During hospital stay, an average of 10 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Apr 2017
- Study start10 Oct 2017
- Primary completion17 Jul 2018
- Study completion17 Jul 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (57)Papers the sponsor has linked to this study.
- Other trials for Meningitis StreptococcalStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oxford University Clinical Research Unit, Vietnam
- Sponsor type
- University, hospital or other
- Collaborators
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, Cho Ray Hospital, University of Liverpool, University of Rochester, Liverpool School of Tropical Medicine
- Responsible party
- Sponsor
- Investigators
- Jeremy Day, MD, Principal investigator, Oxford University Clinical Research Unit
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03112031
- Sponsor's protocol ID
- 28CN
- Status last verified
- Nov 2019
- First submitted
- 29 Mar 2017
- Last updated
- 2 Dec 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009 Feb 20;23(4):525-30. doi: 10.1097/QAD.0b013e328322ffac.
PubMed 19182676Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006 Nov;3(11):e442. doi: 10.1371/journal.pmed.0030442.
PubMed 17132052Chen S, Sorrell T, Nimmo G, Speed B, Currie B, Ellis D, Marriott D, Pfeiffer T, Parr D, Byth K. Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis. 2000 Aug;31(2):499-508. doi: 10.1086/313992. Epub 2000 Sep 7.
PubMed 10987712Chau TT, Mai NH, Phu NH, Nghia HD, Chuong LV, Sinh DX, Duong VA, Diep PT, Campbell JI, Baker S, Hien TT, Lalloo DG, Farrar JJ, Day JN. A prospective descriptive study of cryptococcal meningitis in HIV uninfected patients in Vietnam - high prevalence of Cryptococcus neoformans var grubii in the absence of underlying disease. BMC Infect Dis. 2010 Jul 9;10:199. doi: 10.1186/1471-2334-10-199.
PubMed 20618932Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010 Feb 1;50(3):291-322. doi: 10.1086/649858.
PubMed 20047480Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, Phu NH, Nghia HD, Phong ND, Thai CQ, Thai LH, Chuong LV, Sinh DX, Duong VA, Hoang TN, Diep PT, Campbell JI, Sieu TPM, Baker SG, Chau NVV, Hien TT, Lalloo DG, Farrar JJ. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013 Apr 4;368(14):1291-1302. doi: 10.1056/NEJMoa1110404.
PubMed 23550668Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L, Phuong L, Thwaites G, Van Kinh N, Thuy PT, Chierakul W, Siriboon S, Thiansukhon E, Onsanit S, Supphamongkholchaikul W, Chan AK, Heyderman R, Mwinjiwa E, van Oosterhout JJ, Imran D, Basri H, Mayxay M, Dance D, Phimmasone P, Rattanavong S, Lalloo DG, Day JN; CryptoDex Investigators. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med. 2016 Feb 11;374(6):542-54. doi: 10.1056/NEJMoa1509024.
PubMed 26863355Loyse A, Dromer F, Day J, Lortholary O, Harrison TS. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J Antimicrob Chemother. 2013 Nov;68(11):2435-44. doi: 10.1093/jac/dkt221. Epub 2013 Jun 20.
PubMed 23788479Butts A, Koselny K, Chabrier-Rosello Y, Semighini CP, Brown JC, Wang X, Annadurai S, DiDone L, Tabroff J, Childers WE Jr, Abou-Gharbia M, Wellington M, Cardenas ME, Madhani HD, Heitman J, Krysan DJ. Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. mBio. 2014 Feb 11;5(1):e00765-13. doi: 10.1128/mBio.00765-13.
PubMed 24520056Perez EA, Gandara DR, Edelman MJ, O'Donnell R, Lauder IJ, DeGregorio M. Phase I trial of high-dose tamoxifen in combination with cisplatin in patients with lung cancer and other advanced malignancies. Cancer Invest. 2003;21(1):1-6. doi: 10.1081/cnv-120016397.
PubMed 12643003Bergan RC, Reed E, Myers CE, Headlee D, Brawley O, Cho HK, Figg WD, Tompkins A, Linehan WM, Kohler D, Steinberg SM, Blagosklonny MV. A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin Cancer Res. 1999 Sep;5(9):2366-73.
PubMed 10499606Ducharme J, Fried K, Shenouda G, Leyland-Jones B, Wainer IW. Tamoxifen metabolic patterns within a glioma patient population treated with high-dose tamoxifen. Br J Clin Pharmacol. 1997 Feb;43(2):189-93. doi: 10.1046/j.1365-2125.1997.05029.x.
PubMed 9131952Smith DC, Trump DL. A phase I trial of high-dose oral tamoxifen and CHOPE. Cancer Chemother Pharmacol. 1995;36(1):65-8. doi: 10.1007/BF00685734.
PubMed 7720178Trump DL, Smith DC, Ellis PG, Rogers MP, Schold SC, Winer EP, Panella TJ, Jordan VC, Fine RL. High-dose oral tamoxifen, a potential multidrug-resistance-reversal agent: phase I trial in combination with vinblastine. J Natl Cancer Inst. 1992 Dec 2;84(23):1811-6. doi: 10.1093/jnci/84.23.1811.
PubMed 1359155Wiseman H, Cannon M, Arnstein HR. Observation and significance of growth inhibition of Saccharomyces cerevisiae (A224A) by the anti-oestrogen drug tamoxifen. Biochem Soc Trans. 1989 Dec;17(6):1038-9. doi: 10.1042/bst0171038. No abstract available.
PubMed 2697611
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Trial of Tamoxifen Combined With Amphotericin B and Fluconazole for Cryptococcal Meningitis
- ClinicalTrials.gov ID
- NCT03112031
- Acronym / sponsor ID
- 28CN
- Conditions
- Meningitis Streptococcal, Hiv, Meningitis, Meningoencephalitis
- Keywords
- Tamoxifen, Cryptococcal meningitis, Cryptococcus neoformans, Human immunodeficiency virus
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Oxford University Clinical Research Unit, VietnamUniversity, hospital or other
- Collaborators
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, Cho Ray Hospital, University of Liverpool, University of Rochester, Liverpool School of Tropical Medicine
- Study start
- 10 Oct 2017 (actual)
- Primary completion
- 17 Jul 2018 (actual)
- Study completion
- 17 Jul 2018 (actual)
- First posted
- 13 Apr 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to develop initial efficacy, feasibility, and safety data regarding the use of Tamoxifen in combination with amphotericin B and fluconazole in the treatment of cryptococcal meningitis. The results of the study will inform the design and feasibility of a larger study powered to a survival endpoint. The study hypothesis is that adding tamoxifen to standard antifungal therapy increases the rate of clearance of yeast from cerebrospinal fluid. Increased rates of clearance of yeast from cerebrospinal fluid have previously been associated with improved clinical outcomes, including survival and disability.
Detailed description
A randomized, open-label trial with 2 parallel arms: standard antifungal therapy versus tamoxifen augmented antifungal therapy during the first 2 weeks (induction phase) of treatment. The study will recruit in two sites in Ho Chi Minh City: the Hospital for Tropical Diseases (HTD), and Cho Ray Hospital (CRH). 25 patients will be enrolled into the two study arms (intervention versus control). All anti-fungal administration will be directly observed by ward staff.
Intervention arm: Induction phase treatment (days 1-14): Tamoxifen will be given orally in a dose of 300mg/day for the first 14 days following randomization. It will be administered by nasogastric tube where patients are unconscious. In addition patients will receive amphotericin 1mg/kg once daily iv and fluconazole 800mg once daily orally. The tamoxifen will be administered in the morning combined with amphotericin and fluconazole dose.
Control arm: Induction phase treatment (days 1-14): Patients will receive amphotericin 1mg/kg/day combined with fluconazole 800mg once daily for the first 2 weeks. Amphotericin and fluconazole will be administered simultaneously.
The primary efficacy endpoint will be the rate of clearance of yeast cells from cerebrospinal fluid (CSF) over the first 2 weeks following randomisation. Patients will be followed for 10 weeks, which is conventional in clinical trials in cryptococcal meningitis. After the first 2 weeks of study treatment, all patients will receive fluconazole 800mg/day for 8 further weeks, until the study end. At this point, HIV infected patients will be switched to long term secondary prophylaxis with fluconazole 200mg/day as per standard practice. For HIV uninfected patients, the decision to continue antifungal treatment, and at which dose, will be made on a case by case basis by the attending physician in consultation with the patient.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tamoxifen augmented antifungal therapy | Experimental | Drug: Tamoxifen, Drug: Amphotericin B, Drug: FluconazoleTamoxifen 300mg/day for 2 weeks, combined with standard antifungal therapy (amphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks) |
| Standard antifungal therapy | Active comparator | Drug: Amphotericin B, Drug: FluconazoleAmphotericin B 1mg/kg/day combined with fluconazole 800mg/day for the first 2 weeks followed by fluconazole 800mg/day for 8 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Age ≥ 18 years
- Cryptococcal meningitis (CM) defined as a syndrome consistent with CM and one or more of:
- Informed consent to participate given by patient or acceptable representative
- Known HIV infection status, or patient agrees to HIV testing on this admission
Key exclusion criteria (13 listed)
- Pregnancy or breast-feeding
- History of thromboembolic disease such as pulmonary embolism or deep venous thrombosis
- On anti-coagulant medication
- On medication known to prolong the QT interval other than fluconazole, such as fluoroquinolones or antidepressants.
- Known cardiac conduction defect including long QT syndromes
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TamoxifenAlso: Nolvadex - DTamoxifen will be given orally in a dose of 300mg/day for the first 14 days following randomization. It will be administered by nasogastric tube where patients are unconscious. The Tamoxifen will be administered in the morning combined with amphotericin and fluconazole dose. | Drug | Tamoxifen augmented antifungal therapy |
| Amphotericin BAlso: AmphotretPatients will receive amphotericin 1mg/kg/day i.v. once daily orally for the first 2 weeks. | Drug | Standard antifungal therapy, Tamoxifen augmented antifungal therapy |
| FluconazoleAlso: Zolmed 200Patients will receive fluconazole 800mg once daily orally for the first 2 weeks. Amphotericin and fluconazole will be administered simultaneously. After the first 2 weeks of study treatment, all patients will receive fluconazole 800mg/day for 8 further weeks, until the study end. | Drug | Standard antifungal therapy, Tamoxifen augmented antifungal therapy |
Primary outcome
Early Fungicidal Activity (EFA), i.e. the rate of clearance of yeast from cerebrospinal fluid
Time frame: over the first 2 weeks following randomisation
In the trial, lumbar punctures are scheduled on days 1, 3, 7, 14, and additionally as clinically indicated. Whenever a lumbar puncture is performed, the study team will determine the amount of viable yeast in CSF through culture. Based on the patients' longitudinal quantitative yeast count measurements, EFA will be determined as previously described e.g. see N Engl J Med 2016; 374:542-54
11 secondary outcomes
Survival until 10 weeks after randomization
Time frame: 10 weeks after randomisation
Disability at 10 weeks
Time frame: at 10 weeks
Adverse events
Time frame: During hospital stay, an average of 10 weeks
Rate of IRIS until 10 weeks (in HIV infected patients only)
Time frame: until 10 weeks
Rate of Cryptococcal meningitis relapse
Time frame: until 10 weeks
QT prolongation
Time frame: During hospital stay, an average of 10 weeks
Visual deficit at 10 weeks
Time frame: at 10 weeks
Time to new neurological event or death until 10 weeks
Time frame: until 10 weeks
Longitudinal measurements of intracranial pressure during the first 2 weeks
Time frame: during the first 2 weeks
CD4 count at 10 weeks
Time frame: at 10 weeks
Blood and CSF concentrations of amphotericin, Tamoxifen and fluconazole
Time frame: During hospital stay, an average of 10 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Dec 2019.
- Background: PubMed 19182676Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS. 2009 Feb 20;23(4):525-30. doi: 10.1097/QAD.0b013e328322ffac.
- Background: PubMed 17132052Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006 Nov;3(11):e442. doi: 10.1371/journal.pmed.0030442.
- Background: PubMed 10987712Chen S, Sorrell T, Nimmo G, Speed B, Currie B, Ellis D, Marriott D, Pfeiffer T, Parr D, Byth K. Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group. Clin Infect Dis. 2000 Aug;31(2):499-508. doi: 10.1086/313992. Epub 2000 Sep 7.
- Background: PubMed 20618932Chau TT, Mai NH, Phu NH, Nghia HD, Chuong LV, Sinh DX, Duong VA, Diep PT, Campbell JI, Baker S, Hien TT, Lalloo DG, Farrar JJ, Day JN. A prospective descriptive study of cryptococcal meningitis in HIV uninfected patients in Vietnam - high prevalence of Cryptococcus neoformans var grubii in the absence of underlying disease. BMC Infect Dis. 2010 Jul 9;10:199. doi: 10.1186/1471-2334-10-199.
- Background: PubMed 20047480Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010 Feb 1;50(3):291-322. doi: 10.1086/649858.
- Background: PubMed 23550668Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, Phu NH, Nghia HD, Phong ND, Thai CQ, Thai LH, Chuong LV, Sinh DX, Duong VA, Hoang TN, Diep PT, Campbell JI, Sieu TPM, Baker SG, Chau NVV, Hien TT, Lalloo DG, Farrar JJ. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013 Apr 4;368(14):1291-1302. doi: 10.1056/NEJMoa1110404.
- Background: PubMed 26863355Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L, Phuong L, Thwaites G, Van Kinh N, Thuy PT, Chierakul W, Siriboon S, Thiansukhon E, Onsanit S, Supphamongkholchaikul W, Chan AK, Heyderman R, Mwinjiwa E, van Oosterhout JJ, Imran D, Basri H, Mayxay M, Dance D, Phimmasone P, Rattanavong S, Lalloo DG, Day JN; CryptoDex Investigators. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis. N Engl J Med. 2016 Feb 11;374(6):542-54. doi: 10.1056/NEJMoa1509024.
- Background: PubMed 23788479Loyse A, Dromer F, Day J, Lortholary O, Harrison TS. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J Antimicrob Chemother. 2013 Nov;68(11):2435-44. doi: 10.1093/jac/dkt221. Epub 2013 Jun 20.
- Background: PubMed 24520056Butts A, Koselny K, Chabrier-Rosello Y, Semighini CP, Brown JC, Wang X, Annadurai S, DiDone L, Tabroff J, Childers WE Jr, Abou-Gharbia M, Wellington M, Cardenas ME, Madhani HD, Heitman J, Krysan DJ. Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. mBio. 2014 Feb 11;5(1):e00765-13. doi: 10.1128/mBio.00765-13.
- Background: PubMed 12643003Perez EA, Gandara DR, Edelman MJ, O'Donnell R, Lauder IJ, DeGregorio M. Phase I trial of high-dose tamoxifen in combination with cisplatin in patients with lung cancer and other advanced malignancies. Cancer Invest. 2003;21(1):1-6. doi: 10.1081/cnv-120016397.
- Background: PubMed 10499606Bergan RC, Reed E, Myers CE, Headlee D, Brawley O, Cho HK, Figg WD, Tompkins A, Linehan WM, Kohler D, Steinberg SM, Blagosklonny MV. A Phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer. Clin Cancer Res. 1999 Sep;5(9):2366-73.
- Background: PubMed 9131952Ducharme J, Fried K, Shenouda G, Leyland-Jones B, Wainer IW. Tamoxifen metabolic patterns within a glioma patient population treated with high-dose tamoxifen. Br J Clin Pharmacol. 1997 Feb;43(2):189-93. doi: 10.1046/j.1365-2125.1997.05029.x.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeremy Day, MD principal investigator
Oxford University Clinical Research Unit
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Tamoxifen, Amphotericin B and Fluconazole in people with Meningitis Streptococcal and Hiv, run by Oxford University Clinical Research Unit, Vietnam at 3 sites in Vietnam.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Vietnam. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Early Fungicidal Activity (EFA), i.e. the rate of clearance of yeast from cerebrospinal fluid (time frame: over the first 2 weeks following randomisation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03112031, which also lists 57 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2019.