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Amyotrophic Lateral SclerosisPhase 2RAP-ALSNCT03359538

Rapamycin Treatment for ALS

A Phase 2 study testing Rapamycin in people with Amyotrophic Lateral Sclerosis, run by Azienda Ospedaliero-Universitaria di Modena at 7 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

In the last years research has pointed out potential mechanisms of pathogenesis in ALS including lack of degradation of abnormally accumulated proteins inside motor neurons, and an unbalanced function of the immune system leading to the prevalence of a neurotoxic function over neuroprotection. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Amyotrophic Lateral Sclerosis
What is being tested?
Rapamycin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
63 participants
Where
7 sitesItaly
Study dates
19 Sep 2017to 15 Feb 2022
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 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patient diagnosed with a laboratory supported , clinically "probable" or "definite" amyotrophic lateral sclerosis according to the Revised El Escorial criteria (Brooks, 2000)
  • Familial or sporadic ALS
  • Female or male patients aged between 18 and 75 years old
  • Disease duration from symptoms onset no longer than 18 months at the screening visit
  • Patient treated with a stable dose of Riluzole (100 mg/day) for at least 30 days prior to screening
  • Patients with a weight > 50 kg and a BMI ≥18
Show all 10Show fewer
  • Patient with a FVC ≥ 70 % predicted normal value for gender, height, and age at the screening visit
  • Patient able and willing to comply with study procedures as per protocol
  • Patient able to understand, and capable of providing informed consent at screening visit prior to any protocol-specific procedures
  • Use of effective contraception both for males and females

Who cannot join

  • Prior use of Sirolimus
  • Prior allergy/sensitivity to Sirolimus or macrolides
  • Any medical disorder that would make immunosuppression contraindicated, including but not limited to, acute infections requiring antibiotics, patients with known diagnosis of HIV, tuberculosis, hepatitis B or C infection or history of malignancy
  • Severe comorbidities (heart, renal, liver failure), autoimmune diseases or any type of interstitial lung disease
  • White blood cells<4,000/mm³, platelets count<100,000/mm³, hematocrit<30%
  • Patient who underwent non invasive ventilation, tracheotomy and /or gastrostomy
Show all 9Show fewer
  • Women who are pregnant or breastfeeding
  • Participation in pharmacological studies within the last 30 days before screening
  • Patients with known superoxide dismutase 1 (SOD1) mutation or with familial ALS and a family member carrying SOD1 mutation.

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

Italy7 sites

  • Centro Sla, Irccs A.O.U. S.Martino Ist, Genova

    Genova

  • Centro Clinico Nemo, Fondazione Serena Onlus, Milano

    Milan

  • Centro Sla, Irccs Istituto Carlo Besta, Milano

    Milan

  • Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena

    Modena, 41126

  • Centro Sla, A.O.U. Maggiore Della Carita', Novara

    Novara

  • Centro Sla, Universita' Di Padova

    Padova

  • Centro Sla, Universita' Di Torino

    Torino

Other trials in Italy

About this study

Official title: Rapamycin (Sirolimus) Treatment for Amyotrophic Lateral Sclerosis

In the last years research has pointed out potential mechanisms of pathogenesis in ALS including lack of degradation of abnormally accumulated proteins inside motor neurons, and an unbalanced function of the immune system leading to the prevalence of a neurotoxic function over neuroprotection. These two mechanisms contribute to ALS progression hence representing important therapeutic targets to modify disease expression.

With a phase II clinical trial the investigators aim to study the biological response in ALS treated with Rapamycin, to obtain predictive information for a larger study.

Eight Italian Centres will enroll 63 patients; treatment will be double blinded to patients and physicians, and will last 18 weeks.Follow up will be carried out for 36 months (total duration: 54 weeks).

Read the detailed description

This is a phase II randomized, double-blind, placebo-controlled, multicenter clinical trial for people with ALS.

The aim is to study the biological and clinical effect of Rapamycin (in two different doses) in addition to Riluzole on ALS patients through comparison with patients treated with Riluzole and placebo.

Rapamycin has been shown to enhance proteins degradation, and this has been associated with beneficial effects in models of neurodegeneration. Its immunomodulatory effects are also well established, notably the ability to suppress inflammatory neurotoxic responses mediated by T cells. As ALS is characterized by heterogeneous pathology and protein accumulation, some patients may respond to therapies that accelerate the clearance of abnormally accumulated proteic aggregates, while suppressing neurotoxic immune elements.

Subjects will be enrolled in 3 groups of 21 subjects; treatment will be double blinded to patients and physicians, and will last 18 weeks. Active treatment will include oral Rapamycin at different doses: Rapamycin 1mg/m2/day or Rapamycin 2mg/m2/day. Rapamycin will be administered at fast, in the morning, once a day. Rapamycin levels will be measured (HPLC) to avoid toxicity (>15 ng/ml), but treating neurologists will have no access to blood laboratory data. Dosages will be adjusted accordingly and sham adjustments will be done in the placebo Group too. Post-treatment follow up will be 36 weeks. Globally the study will lasts 24 months. To monitor adverse events, examination and routine laboratory work (cell count, lipids and protein profile, kidney and liver function, C reactive protein) will be performed before taking Rapamycin/placebo. Non-routine laboratory studies include quantification and characterization of Tregs, lymphocytes phenotype, mTOR (mammilian target of rapamycin) downstream pathway activation in peripheral blood mononuclear cells (PBMC), inflammasome components in PBMC and proinflammatory cytokine production in monocytes, peripheral biomarkers. Cerebrospinal fluid (CSF) will be taken at baseline and at week 18 to measure neurofilaments and to dose Rapamycin to understand whether sufficient levels of Rapamycin can be found in the central nervous system (CNS).

Being tested
Rapamycin, Placebo Oral Tablet
Keywords
Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Rapamycin
Medical subject headings
Amyotrophic Lateral Sclerosis, Motor Neuron Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RapamycinDrug

    Also called Rapamune

    tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage

  • Placebo Oral TabletDrug

    tablets containing Rapamycin/placebo will be administered based on body surface area and adjusted taking into consideration plasma rapamycin dosage

Study groups in NCT03359538
Study groupRoleWhat they receive
placeboPlacebo comparatorPatients assigned to this arm will take Riluzole as usual + placebo tablets
Receives: Drug: Placebo Oral Tablet
Rapamycin 1 mg/m2Active comparatorPatients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 1 mg/m2/day
Receives: Drug: Rapamycin; Drug: Placebo Oral Tablet
Rapamycin 2 mg/m2Active comparatorPatients assigned to this arm will take Riluzole as usual + tablets corresponding to a Rapamycin dose of 2 mg/m2/day
Receives: Drug: Rapamycin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. T-reg number

    Proportion of patients exhibiting a positive response (considered as increase in Treg of at least 30%), comparing baseline and treatment end between Rapamycin and placebo arm

    Measured: comparison between baseline and treatment end (week 18)

Secondary outcomes (11)

  1. Number of serious adverse events (SAEs) and AEs in placebo and treatment arms

    Rapamycin safety and tolerability in a cohort of ALS patients

    Measured: At week 18 and 54

  2. Rapamycin capacity to pass through blood brain barrier

    HPLC-MS (mass spectrometry) dosage of Rapamycin in CSF in placebo and treatment arm will be performed at treatment end

    Measured: At week 18

  3. Rapamycin efficacy in inhibiting Mtor pathway

    Assessment of the phosphorylation of the S6 ribosomal protein (S6RP) comparing Rapamycin arms and placebo arm

    Measured: At week 8-18-30-54

  4. Changes in activation and homing capabilities of different T, B, natural killer (NK) cell subpopulations

    Change from baseline to each time point (week 8, 18, 30, and 54) of the activation and homing capabilities of different T, B, NK cell subpopulations comparing Rapamycin arms and placebo arm.

    Measured: At baseline and at week 8-18-30-54

  5. Changes in CSF neurofilaments

    Changes from baseline to week 18 of the levels of neurofilaments in CSF in treatment and placebo arms

    Measured: Baseline and week 18

  6. Changes in blood biomarkers

    Changes from baseline to week 8-18-30.54 of the levels of neurofilaments and vitamin D in treatment and placebo arms

    Measured: Baseline, week 8-18-30-54

  7. Rapamycin-induced changes in inflammatory status

    Changes from baseline to each time point (week 8, 18, 30, and 54) in inflammatory status (cytokines and cells) (molecular analysis of the inflammasome system) comparing Rapamycin arms and placebo arm

    Measured: Baseline and week 8-18-30-54

  8. Changes in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised

    ALSFRS-R score changes from baseline to week 4, 8, 12, 18, 30, 42 and week 54 in treatment and placebo arms.

    Measured: Up to week 54

  9. Tracheostomy-free survival rate

    Overall survival from randomization to date of death or tracheostomy

    Measured: Up to week 54

  10. Changes in Forced vital capacity (FVC)

    Changes in FVC score from baseline to week 4, 8, 12, 18, 30, 42, 54 in treatment and placebo arms.

    Measured: Up to week 54

  11. Change in quality of life

    Changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) from baseline to week 8, 18, 30 and week 54, in placebo and treatment arms

    Measured: From baseline to week 8, 18, 30 and week 54

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Dec 2017
  2. Study start19 Sep 2017
  3. Primary completion15 Dec 2020
  4. Study completion15 Feb 2022

Resources

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
Double blind
Who is masked
Participant, Investigator
Enrolment
63 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03359538
Sponsor's protocol ID
RAP-ALS
Acronym
RAP-ALS
Status last verified
Sep 2024
First submitted
8 Nov 2017
Last updated
19 Sep 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Barmada SJ, Serio A, Arjun A, Bilican B, Daub A, Ando DM, Tsvetkov A, Pleiss M, Li X, Peisach D, Shaw C, Chandran S, Finkbeiner S. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol. 2014 Aug;10(8):677-85. doi: 10.1038/nchembio.1563. Epub 2014 Jun 29.

    PubMed 24974230

  • Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011 May;134(Pt 5):1293-314. doi: 10.1093/brain/awr074.

    PubMed 21596768

  • Buchan JR, Kolaitis RM, Taylor JP, Parker R. Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. Cell. 2013 Jun 20;153(7):1461-74. doi: 10.1016/j.cell.2013.05.037.

    PubMed 23791177

  • Caccamo A, Majumder S, Deng JJ, Bai Y, Thornton FB, Oddo S. Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J Biol Chem. 2009 Oct 2;284(40):27416-24. doi: 10.1074/jbc.M109.031278. Epub 2009 Aug 3.

    PubMed 19651785

  • Chio A, Hammond ER, Mora G, Bonito V, Filippini G. Development and evaluation of a clinical staging system for amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2015 Jan;86(1):38-44. doi: 10.1136/jnnp-2013-306589. Epub 2013 Dec 13.

    PubMed 24336810

  • Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ, Ren Z, Keebler J, Han Y, Levy SE, Boone BE, Wimbish JR, Waite LL, Jones AL, Carulli JP, Day-Williams AG, Staropoli JF, Xin WW, Chesi A, Raphael AR, McKenna-Yasek D, Cady J, Vianney de Jong JM, Kenna KP, Smith BN, Topp S, Miller J, Gkazi A; FALS Sequencing Consortium; Al-Chalabi A, van den Berg LH, Veldink J, Silani V, Ticozzi N, Shaw CE, Baloh RH, Appel S, Simpson E, Lagier-Tourenne C, Pulst SM, Gibson S, Trojanowski JQ, Elman L, McCluskey L, Grossman M, Shneider NA, Chung WK, Ravits JM, Glass JD, Sims KB, Van Deerlin VM, Maniatis T, Hayes SD, Ordureau A, Swarup S, Landers J, Baas F, Allen AS, Bedlack RS, Harper JW, Gitler AD, Rouleau GA, Brown R, Harms MB, Cooper GM, Harris T, Myers RM, Goldstein DB. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015 Mar 27;347(6229):1436-41. doi: 10.1126/science.aaa3650. Epub 2015 Feb 19.

    PubMed 25700176

  • Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 2008 Jan 22;5(1):e8. doi: 10.1371/journal.pmed.0050008.

    PubMed 18215105

  • Deivasigamani S, Verma HK, Ueda R, Ratnaparkhi A, Ratnaparkhi GS. A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis. Biol Open. 2014 Oct 31;3(11):1127-38. doi: 10.1242/bio.201410066.

    PubMed 25361581

  • Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. doi: 10.1038/nature08221. Epub 2009 Jul 8.

    PubMed 19587680

  • Kimura F, Fujimura C, Ishida S, Nakajima H, Furutama D, Uehara H, Shinoda K, Sugino M, Hanafusa T. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006 Jan 24;66(2):265-7. doi: 10.1212/01.wnl.0000194316.91908.8a.

    PubMed 16434671

  • Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006 Jun 15;441(7095):880-4. doi: 10.1038/nature04723. Epub 2006 Apr 19.

    PubMed 16625205

  • Lattante S, de Calbiac H, Le Ber I, Brice A, Ciura S, Kabashi E. Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD. Hum Mol Genet. 2015 Mar 15;24(6):1682-90. doi: 10.1093/hmg/ddu580. Epub 2014 Nov 19.

    PubMed 25410659

  • Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014 Oct 22;84(2):275-91. doi: 10.1016/j.neuron.2014.09.034. Epub 2014 Oct 22.

    PubMed 25374355

  • Mantovani S, Garbelli S, Pasini A, Alimonti D, Perotti C, Melazzini M, Bendotti C, Mora G. Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J Neuroimmunol. 2009 May 29;210(1-2):73-9. doi: 10.1016/j.jneuroim.2009.02.012.

    PubMed 19307024

  • Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004 Jun;36(6):585-95. doi: 10.1038/ng1362. Epub 2004 May 16.

    PubMed 15146184

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Rapamycin in people with Amyotrophic Lateral Sclerosis, run by Azienda Ospedaliero-Universitaria di Modena at 7 sites in Italy.

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 10 inclusion and 9 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 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Italy. 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 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?

T-reg number (time frame: comparison between baseline and treatment end (week 18)). 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 NCT03359538, which also lists 21 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 19 Sep 2024.

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