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Phase I/IIa Trial of scAAV1.tMCK.NTF3 for Treatment of CMT1A

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ClinicalTrials.gov Identifier: NCT03520751
Recruitment Status : Not yet recruiting
First Posted : May 10, 2018
Last Update Posted : October 16, 2019
Sponsor:
Information provided by (Responsible Party):
Zarife Sahenk, Nationwide Children's Hospital

Tracking Information
First Submitted Date  ICMJE April 20, 2018
First Posted Date  ICMJE May 10, 2018
Last Update Posted Date October 16, 2019
Estimated Study Start Date  ICMJE January 2020
Estimated Primary Completion Date April 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 27, 2018)
Safety based on number of participants with adverse events. [ Time Frame: 2 years ]
AEs will be monitored and scored for severity and relatedness to the study article.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03520751 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 27, 2018)
  • Efficacy - the ability to halt the decline in functional and sensory abilities [ Time Frame: Screening, Day 90, 6 months, 1yr, 18 months, 2 yrs ]
    CMT Pediatric Scale. Efficacy will be defined as the ability to halt the decline in functional and sensory abilities as measured by the CMTPedS at 2 years post gene transfer. This 11 item scale, developed by the Inherited Neuropathies Consortium, underwent validation testing in patients aged 3-20 years with CMT and generates a linear score of disability.
  • Physical Therapy Assessments The 100 Meter Timed Test (100m) [ Time Frame: Screening, Day 90, 6 months, 1yr, 18 months, 2 yrs ]
    The 100 Meter Timed Test will be an exploratory outcome for this study.
  • Electrophysiological testing [ Time Frame: Screening, Day 90, 6 months, 1yr, 18 months, 2 yrs ]
    Measurement of ulnar sensory nerve amplitude and compound muscle action potential (CMAP); amplitude of the ulnar nerve (recorded from the abductor digiti minimi muscle) and the peroneal nerve (recorded from the tibialis anterior muscle) and sensory and motor conduction velocities.
  • Sensory testing using semi-quantitative Rydel Seiffer tuning fork, Semmes-Weinstein Monofilaments and Neurotips [ Time Frame: Screening, Day 90, 6 months, 1yr, 18 months, 2 yrs ]
    Perceptions of touch pressure, pricking pain and vibration will be graded on the index finger and the great toe as normal (0), decreased (1), or absent (2). In addition, the level of discrimination change for sensory modalities will be recorded in the dominant upper and lower limbs as normal (0), diminished or absent in fingers or toes (1), between fingers/toes and wrist or ankle (2), between wrist/ankle and mid-forearm or mid-calf level (3), between mid-forearm/mid-calf and elbow or knee (4) and above the level of elbow or knee (5).
  • Visual analog scale (VAS) [ Time Frame: Screening, Day 90, 6 months, 1yr, 18 months, 2 yrs ]
    The visual analog scale (VAS) of pain intensity consists of a line, most often 100 mm long, with 2 descriptors representing extremes of pain intensity (e.g., no pain and extreme pain) at each end. Patients rate their pain intensity by making a mark somewhere on the line that represents their pain intensity and the VAS is scored by measuring the distance from the "no pain" end of the line.
  • Short Form Health Survey (SF-36) [ Time Frame: Screening, Day 90, 6 months, 1yr, 18 months, 2 yrs ]
    The Short Form Health Survey (SF-36) will be used as a quality of life document to monitor and compare disease burden pre and post-treatment. The SF-36 is a multi-purpose, short-form health survey with only 36 questions. It yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference-based health utility index.
  • NT-3 levels [ Time Frame: Screening, Day 7-2 yrs ]
    Circulating NT-3 levels will be measured by ELISA.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase I/IIa Trial of scAAV1.tMCK.NTF3 for Treatment of CMT1A
Official Title  ICMJE Phase I/IIa Trial Evaluating scAAV1.tMCK.NTF3 for Treatment of Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
Brief Summary This clinical trial is an open-label, one-time injection ascending dose study in which scAAV1.tMCK.NTF3 will be administered by intramuscular injections into muscles in both legs in CMT1A subjects with PMP22 gene duplication. Cohort 1 will include three subjects ages 18 to 35 years receiving (2e12 vg/kg), and Cohort 2 will include six subjects ages 15 to 35 years old receiving (6e12 vg/kg).
Detailed Description This clinical trial is an open-label, one-time injection ascending dose study in which scAAV1.tMCK.NTF3 will be administered by intramuscular injections into medial and lateral heads of gastrocnemius and tibialis anterior muscles in both legs in CMT1A subjects with PMP22 gene duplication. Nine CMT1A patients, 15 to 35 years of age will be enrolled into one of two cohorts in this trial. The first cohort will consist of subjects that are 18 to 35 years of age. The first three adult subjects will be enrolled at a low-minimally effective dose (2e12 vg/kg) distributed bilaterally between both limbs in Cohort 1. An additional six subjects, ages 15 to 35, will be enrolled with a 3-fold dose escalation (6e12 vg/kg) in Cohort 2. Post-gene transfer monitoring will include follow up visits on days 7, 14, 30, 60, 90, 120, and months 6, 9, 12, 15, 18 and 24 following gene transfer. Safety is the primary endpoint for this clinical gene transfer trial. Stopping criteria are based on development of unacceptable toxicity defined as the occurrence of any one Grade III or higher, unanticipated, treatment-related toxicity. The secondary endpoint is efficacy defined as halting of the decline in abilities measured by the CMT Pediatric Scale (CMTPedS) at 2 years post gene transfer. The CMTPedS is an 11-item scale comprised of the Functional Dexterity Test, Nine-Hole Peg Test (9HPT), hand grip, foot plantarflexion, and foot dorsiflexion strength using handheld myometry, pinprick and vibration sensation, the Bruininks Oseretsky Test- Balance assessment, gait assessment, long jump, and six-minute walk test (6MWT). Exploratory outcome measures will include 100 meter timed test (100M), peroneal and ulnar CMAP amplitude and sensory and motor conduction velocities, a revised sensory testing to increase sensitivity for pinprick, touch-test and vibration assessments, visual analogue scales for pain and fatigue, Short Form Health Survey (SF-36) as Quality of Life measure, and circulating NT-3 levels.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Charcot-Marie-Tooth Neuropathy Type 1A
Intervention  ICMJE Drug: scAAV1.tMCK.NTF3
gene vector
Other Name: Neurotrophin Factor 3 (NTF3) vector
Study Arms  ICMJE
  • Experimental: Low dose (2e12 vg/kg)
    Three patients age 18-35 will receive intramuscular injection of recombinant AAV1 carrying a human NFT3 gene under the control of the tMCK promoter (scAAV1.tMCK.NTF3) distributed bilaterally between both limbs at low dose (2e12 vg/kg).
    Intervention: Drug: scAAV1.tMCK.NTF3
  • Experimental: Dose escalation (6e12 vg/kg)
    Six patients age 15-35 will receive Intramuscular injection of recombinant AAV1 carrying a human NFT3 gene under the control of the tMCK promoter (scAAV1.tMCK.NTF3) distributed bilaterally between both limbs in a 3-fold dose escalation (6e12 vg/kg)
    Intervention: Drug: scAAV1.tMCK.NTF3
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 27, 2018)
9
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 1, 2020
Estimated Primary Completion Date April 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects 15- 35 years old inclusive with CMT1A will be enrolled (Cohort 1 will only include subjects that are 18 to 35 years of age)
  • Must exhibit a 1.5 Mb duplication at 17p11.2 inclusive of the peripheral myelin protein 22 (PMP22) gene
  • Males and females of any ethnic or racial group
  • Must exhibit weakness of the ankle dorsiflexion muscle (but has full ROM against gravity and is able to stand on heels 3 seconds or greater)
  • Abnormal nerve conduction velocities
  • Ability to cooperate for clinical evaluation and repeat nerve conduction studies
  • Willingness of sexually active subjects to practice a reliable method of contraception during the study

Exclusion Criteria:

  • Active viral infection based on clinical observations or serological evidence of HIV, or Hepatitis B or C infection
  • Ongoing immunosuppressive therapy or immunosuppressive therapy within 6 months of starting the trial (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin)
  • Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
  • Subjects with AAV1 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay
  • Subjects with circulating anti-NT-3 titers ≥ 1:50 as determined by ELISA immunoassay
  • Treat with any investigational medication within 30 days before the infusion of study drug
  • Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm)
  • Any medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's wellbeing, safety, or clinical interpretability
  • Ankle contractures or surgeries preventing proper muscle strength testing
  • Pregnancy or lactation (females subjects will be tested for pregnancy)
  • Limb surgery in the past six months
  • Severe infection (e.g. pneumonia, pyelonephritis, or meningitis) within 4 weeks before gene transfer visit (enrollment may be postponed)
  • Anyone unwilling to disclose study participation with primary care physician and other medical providers.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years to 35 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shelli Farley (614)722-2654 Shelli.Farley@NationwideChildrens.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03520751
Other Study ID Numbers  ICMJE IRB17-01287
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Zarife Sahenk, Nationwide Children's Hospital
Study Sponsor  ICMJE Nationwide Children's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Zarife Sahenk, MD., PhD. Nationwide Children's Hospital
PRS Account Nationwide Children's Hospital
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP