Type 1 DiabetesPhase 1NCT02384889
DFMO in Children With Type 1 Diabetes
A Phase 1 study testing Difluoromethylornithine in people with Type 1 Diabetes, run by Indiana University at 3 sites in United States.
Trial summary
This study is a multicenter, double-blind, placebo-controlled, 2:1 randomly assigned, phase 1 clinical trial for individuals with type 1 diabetes. It is a blinded dose-ranging study enrolling patients with new onset type 1 diabetes with documented continued residual C-peptide production. Read more about this study
- Who is it for?
- Ages 12 to 40 years
- Conditions the study is for
- Type 1 Diabetes
- What is being tested?
- Difluoromethylornithine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 41 participants
- Where
- 3 sitesUnited States
- Study dates
- Apr 2015to 6 Jan 2020
- Phase
- Phase 1
- 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 12 to 40 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Males and females 12-40 years of age with a clinical diagnosis of T1D within 2 - 8 months after diagnosis at the time of visit 2.
- Random non-fasting C-peptide level of >0.2 pmol/mL at visit 1.
- Positive for any one of the following diabetes-related autoantibodies (mIAA, GADA, IA-2A, or ZnT8A)
- Treatment naïve of any immunomodulatory agent
- Normal hearing at screening, defined as acceptable results of pure-tone audiometry (<20 decibel [dB] baseline thresholds for frequencies 250, 500, 1000, and 2000 Hz
Who cannot join
- Presence of severe, active disease that interferes with dietary intake or requires the use of chronic medication, with the exception of well-controlled hypothyroidism and mild asthma not requiring oral steroids. Presence of any psychiatric disorder that will affect ability to participate in study.
- Diabetes other than T1D
- Chronic illness known to affect glucose metabolism (e.g. Cushing syndrome, polycystic ovarian disorder, cystic fibrosis) or taking medications that affect glucose metabolism (e.g. steroids, metformin)
- Inability to swallow pills
- Psychiatric impairment or current use of anti-psychotic medication
- Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results.
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- Hematologic abnormalities at screening (anemia, leukopenia (particularly neutropenia), or thrombocytopenia)
- Impaired renal function (assessed by history and BUN/Creatinine, DFMO is renally excreted)
- Female participants of child-bearing age must not be pregnant and agree to use an effective form of birth control or be abstinent during the study period.
- BMI >95% for age and sex
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Women and Children's Hospital of Buffalo
Buffalo, New York, 14222
Riley Hospital for Children
Indianapolis, Indiana, 46202
Children's Hospital of Wisconsin
Wauwatosa, Wisconsin, 53226
About this study
Official title: Targeting Polyamines Using DFMO in Persons With Type 1 Diabetes: A Randomized, Double-Masked, Placebo-Controlled Phase I Study to Evaluate the Safety, Tolerability, and Initial Pharmacodynamics of Multiple Ascending Doses
This study is a multicenter, double-blind, placebo-controlled, 2:1 randomly assigned, phase 1 clinical trial for individuals with type 1 diabetes. It is a blinded dose-ranging study enrolling patients with new onset type 1 diabetes with documented continued residual C-peptide production. After a 4 week screening and run-in period during which eligibility will be determined and glycemic control optimized, subjects will have a 3-month double-masked treatment period with either DFMO or placebo. After a 3 month wash-out period the durability of effect will be assessed. Subjects will be randomly assigned (6 to DFMO; 3 to placebo in each cohort) to 1 of 4 sequential dose cohorts.
Read the detailed description
This study is repurposing alpha difluoromethylornithine (DFMO) in order to characterize its effects in persons with new onset type 1 diabetes. In preliminary studies in mice, inhibition of polyamine synthesis with DFMO preserved β-cell insulin production and delayed diabetes onset. Polyamine modulation has the potential to improve β cell health in persons with T1D. The investigators propose that decreasing polyamine synthesis in persons with new onset T1D will improve markers of ß cell health and function.
This double-masked, placebo-controlled dose-finding randomized multiple ascending dose study will include a 1-month screening period; a 3-month double-masked treatment period; and a 3-month follow-up period. Subjects will be randomly assigned to 1 of 4 sequential dose cohorts: DFMO at nominal (starting) doses of 125 mg/m2 per day, 250 mg/m2 per day, 500 mg/m2 per day, and then 750 mg/m2 per day. Dose escalation will be done based upon whether any dose limiting toxicities are observed and whether any suggestion of effect on biomarkers of β-cell stress is observed. At a maximum dose, the cohort will be expanded in order to estimate biomarker activity. If there is no suggestion of effect and no dose-limiting toxicity 750 mg/m2 per day, a 750 mg per day group will be enrolled. Regardless of the dose we expand, the investigators will evaluate efficacy of treatment on the primary and secondary outcomes. The primary outcome endpoint in this study will be the safety of the doses. In particular, the dose-limiting toxicities known to be potential side effects of DFMO (thrombocytopenia, neutropenia, anemia, audiometric impairment) will be reviewed and monitored by an internal safety review committee before each cohort is enrolled. Secondary outcomes will include biomarkers of beta cell stress, measures of insulin production/glycemia. Exploratory outcomes will include flow cytometry assessment of B- and T-cell subsets, quantification of polyamine intake and excretion, and pharmacokinetic DFMO concentrations. Completion of this study will facilitate future work in studies of DFMO or other inhibitors of pathways that influence intracellular polyamine levels, including non-steroidal inflammatory agents, and novel polyamine transport inhibitors. .
- Conditions
- Type 1 Diabetes
- Being tested
- Difluoromethylornithine, Placebo
- Medical subject headings
- Diabetes Mellitus, Type 1
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DifluoromethylornithineDrug
Also called DFMO
Active Therapy with DFMO
PlaceboDrug
Also called Comparitor
Placebo Comparitor
| Study group | Role | What they receive |
|---|---|---|
| Difluoromethylornithine | Experimental | Subjects may be given daily dose of DFMO Receives: Drug: Difluoromethylornithine |
| Placebo | Placebo comparator | Subjects may be given daily dose of placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants with Dose Limiting Toxicities
Low platelet counts, low white blood cell counts, low hemoglobin, severe abdominal pain/diarrhea, hearing loss
Measured: 6 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Mar 2015 (estimated)
- Study startApr 2015
- Primary completion7 Oct 2019
- Study completion6 Jan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Type 1 DiabetesStudies of the same condition, open and under way.
- More trials run by Indiana UniversityThe sponsor's other registered studies.
- 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 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 41 participants (actual)
Sponsor and investigators
- Lead sponsor
- Indiana University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Linda DiMeglio, MD, Indiana University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02384889
- Sponsor's protocol ID
- 1411735324
- Status last verified
- Sep 2021
- First submitted
- 12 Feb 2015
- Last updated
- 5 Sep 2021
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Sims EK, Kulkarni A, Hull A, Woerner SE, Cabrera S, Mastrandrea LD, Hammoud B, Sarkar S, Nakayasu ES, Mastracci TL, Perkins SM, Ouyang F, Webb-Robertson BJ, Enriquez JR, Tersey SA, Evans-Molina C, Long SA, Blanchfield L, Gerner EW, Mirmira RG, DiMeglio LA. Inhibition of polyamine biosynthesis preserves beta cell function in type 1 diabetes. Cell Rep Med. 2023 Nov 21;4(11):101261. doi: 10.1016/j.xcrm.2023.101261. Epub 2023 Nov 1.
PubMed 37918404Robertson MA, Padgett LR, Fine JA, Chopra G, Mastracci TL. Targeting polyamine biosynthesis to stimulate beta cell regeneration in zebrafish. Islets. 2020 Sep 2;12(5):99-107. doi: 10.1080/19382014.2020.1791530. Epub 2020 Jul 25.
PubMed 32715853
Study at a glance
From the registry record, last updated by the sponsor on 5 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeting Polyamines Using DFMO in Persons With Type 1 Diabetes: A Randomized, Double-Masked, Placebo-Controlled Phase I Study to Evaluate the Safety, Tolerability, and Initial Pharmacodynamics of Multiple Ascending Doses
- ClinicalTrials.gov ID
- NCT02384889
- Acronym / sponsor ID
- 1411735324
- Conditions
- Type 1 Diabetes
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 41 participants (actual)
- Lead sponsor
- Indiana UniversityUniversity, hospital or other
- Study start
- Apr 2015
- Primary completion
- 7 Oct 2019 (actual)
- Study completion
- 6 Jan 2020 (actual)
- First posted
- 10 Mar 2015 (estimated)
- 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.
This study is a multicenter, double-blind, placebo-controlled, 2:1 randomly assigned, phase 1 clinical trial for individuals with type 1 diabetes. It is a blinded dose-ranging study enrolling patients with new onset type 1 diabetes with documented continued residual C-peptide production. After a 4 week screening and run-in period during which eligibility will be determined and glycemic control optimized, subjects will have a 3-month double-masked treatment period with either DFMO or placebo. After a 3 month wash-out period the durability of effect will be assessed. Subjects will be randomly assigned (6 to DFMO; 3 to placebo in each cohort) to 1 of 4 sequential dose cohorts.
Detailed description
This study is repurposing alpha difluoromethylornithine (DFMO) in order to characterize its effects in persons with new onset type 1 diabetes. In preliminary studies in mice, inhibition of polyamine synthesis with DFMO preserved β-cell insulin production and delayed diabetes onset. Polyamine modulation has the potential to improve β cell health in persons with T1D. The investigators propose that decreasing polyamine synthesis in persons with new onset T1D will improve markers of ß cell health and function.
This double-masked, placebo-controlled dose-finding randomized multiple ascending dose study will include a 1-month screening period; a 3-month double-masked treatment period; and a 3-month follow-up period. Subjects will be randomly assigned to 1 of 4 sequential dose cohorts: DFMO at nominal (starting) doses of 125 mg/m2 per day, 250 mg/m2 per day, 500 mg/m2 per day, and then 750 mg/m2 per day. Dose escalation will be done based upon whether any dose limiting toxicities are observed and whether any suggestion of effect on biomarkers of β-cell stress is observed. At a maximum dose, the cohort will be expanded in order to estimate biomarker activity. If there is no suggestion of effect and no dose-limiting toxicity 750 mg/m2 per day, a 750 mg per day group will be enrolled. Regardless of the dose we expand, the investigators will evaluate efficacy of treatment on the primary and secondary outcomes. The primary outcome endpoint in this study will be the safety of the doses. In particular, the dose-limiting toxicities known to be potential side effects of DFMO (thrombocytopenia, neutropenia, anemia, audiometric impairment) will be reviewed and monitored by an internal safety review committee before each cohort is enrolled. Secondary outcomes will include biomarkers of beta cell stress, measures of insulin production/glycemia. Exploratory outcomes will include flow cytometry assessment of B- and T-cell subsets, quantification of polyamine intake and excretion, and pharmacokinetic DFMO concentrations. Completion of this study will facilitate future work in studies of DFMO or other inhibitors of pathways that influence intracellular polyamine levels, including non-steroidal inflammatory agents, and novel polyamine transport inhibitors. .
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Difluoromethylornithine | Experimental | Drug: DifluoromethylornithineSubjects may be given daily dose of DFMO |
| Placebo | Placebo comparator | Drug: PlaceboSubjects may be given daily dose of placebo |
Who may qualify
- Ages
- 12 to 40 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- Males and females 12-40 years of age with a clinical diagnosis of T1D within 2 - 8 months after diagnosis at the time of visit 2.
- Random non-fasting C-peptide level of >0.2 pmol/mL at visit 1.
- Positive for any one of the following diabetes-related autoantibodies (mIAA, GADA, IA-2A, or ZnT8A)
- Treatment naïve of any immunomodulatory agent
- Normal hearing at screening, defined as acceptable results of pure-tone audiometry (<20 decibel [dB] baseline thresholds for frequencies 250, 500, 1000, and 2000 Hz
Key exclusion criteria (10 listed)
- Presence of severe, active disease that interferes with dietary intake or requires the use of chronic medication, with the exception of well-controlled hypothyroidism and mild asthma not requiring oral steroids. Presence of any psychiatric disorder that will affect ability to participate in study.
- Diabetes other than T1D
- Chronic illness known to affect glucose metabolism (e.g. Cushing syndrome, polycystic ovarian disorder, cystic fibrosis) or taking medications that affect glucose metabolism (e.g. steroids, metformin)
- Inability to swallow pills
- Psychiatric impairment or current use of anti-psychotic medication
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 |
|---|---|---|
| DifluoromethylornithineAlso: DFMOActive Therapy with DFMO | Drug | Difluoromethylornithine |
| PlaceboAlso: ComparitorPlacebo Comparitor | Drug | Placebo |
Primary outcome
Number of Participants with Dose Limiting Toxicities
Time frame: 6 month
Low platelet counts, low white blood cell counts, low hemoglobin, severe abdominal pain/diarrhea, hearing loss
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 5 Sep 2021.
- Derived from this study: PubMed 37918404Sims EK, Kulkarni A, Hull A, Woerner SE, Cabrera S, Mastrandrea LD, Hammoud B, Sarkar S, Nakayasu ES, Mastracci TL, Perkins SM, Ouyang F, Webb-Robertson BJ, Enriquez JR, Tersey SA, Evans-Molina C, Long SA, Blanchfield L, Gerner EW, Mirmira RG, DiMeglio LA. Inhibition of polyamine biosynthesis preserves beta cell function in type 1 diabetes. Cell Rep Med. 2023 Nov 21;4(11):101261. doi: 10.1016/j.xcrm.2023.101261. Epub 2023 Nov 1.
- Derived from this study: PubMed 32715853Robertson MA, Padgett LR, Fine JA, Chopra G, Mastracci TL. Targeting polyamine biosynthesis to stimulate beta cell regeneration in zebrafish. Islets. 2020 Sep 2;12(5):99-107. doi: 10.1080/19382014.2020.1791530. Epub 2020 Jul 25.
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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.
The record lists no contact. Use the official record to reach the sponsor.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Difluoromethylornithine in people with Type 1 Diabetes, run by Indiana University at 3 sites in United States.
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 5 inclusion and 10 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 5 Sep 2021. 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 United States. 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. Some participants in this study may receive a placebo. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Number of Participants with Dose Limiting Toxicities (time frame: 6 month). 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 NCT02384889, which also lists 2 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 5 Sep 2021.