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Safety, Tolerability, and Efficacy of BVS857 in Patients With Spinal and Bulbar Muscular Atrophy

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ClinicalTrials.gov Identifier: NCT02024932
Recruitment Status : Completed
First Posted : December 31, 2013
Results First Posted : August 11, 2017
Last Update Posted : April 10, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE December 29, 2013
First Posted Date  ICMJE December 31, 2013
Results First Submitted Date  ICMJE April 12, 2017
Results First Posted Date  ICMJE August 11, 2017
Last Update Posted Date April 10, 2019
Actual Study Start Date  ICMJE February 4, 2014
Actual Primary Completion Date April 13, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 12, 2017)
  • Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability [ Time Frame: After 78 days in Part A and after 85 days in Part B. ]
    Safety was monitored throughout the study.
  • Number of Mild, Moderate and Severe Adverse Events as a Measure of Safety and Tolerability [ Time Frame: After 78 days in Part A and after 85 days in Part B. ]
    Safety was monitored throughout the study.
  • Mean Percent Change From Baseline in Thigh Muscle Volume in Part B, Cohort 5 [ Time Frame: Baseline, Day 85 ]
    Thigh muscle volume was assessed by magnetic resonance imaging (MRI). Change from baseline was calculated from the ratio of the post-baseline mean value to the baseline mean value: [(Day 85/baseline) - 1)] x 100. A positive change from baseline indicates improvement.
Original Primary Outcome Measures  ICMJE
 (submitted: December 29, 2013)
  • Number of patients with adverse events as a measure of safety and tolerability [ Time Frame: After 78 days in Part A and after 85 days in Part B. ]
  • Number of Mild, Moderate and Severe Adverse Events as a Measure of Safety and Tolerability [ Time Frame: After 78 days in Part A and after 85 days in Part B. ]
  • Change in thigh muscle volume [ Time Frame: Baseline and Day 85 in Part B. ]
Change History Complete list of historical versions of study NCT02024932 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 12, 2017)
  • Mean Change From Baseline in Score on the Adult Myopathy Assessment Tool (AMAT) in Part B, Cohort 5 [ Time Frame: Baseline, Day 85 ]
    The AMAT rated physical function and muscle endurance, with higher scores indicating better performance. The tool includes 7 timed functional tasks rated on a scale from 0 - 21 and 6 endurance tasks rated on a scale from 0 - 24. The range for the total score was from 0 (worst) to 45 (best). A positive change from baseline indicates improvement.
  • Mean Change From Baseline in Total Lean Body Mass (LBM) in Part B, Cohort 5 [ Time Frame: Baseline, Day 85 ]
    LBM was assessed by dual-energy X-ray (DXA) absorptiometry. A positive change from baseline indicate improvement.
  • Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part A, Cohort 1 [ Time Frame: Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part A, Cohort 2 [ Time Frame: Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part A, Cohort 1 [ Time Frame: Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part A, Cohort 2 [ Time Frame: Day 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) in Part A, Cohort 1 [ Time Frame: Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) in Part A, Cohort 2 [ Time Frame: Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Plasma Concentration-time Curve From Zero to 48 Hours (AUC0_48h) in Part A, Cohort 1 [ Time Frame: Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Plasma Concentration-time Curve From Zero to 48 Hours (AUC0_48h) in Part A, Cohort 2 [ Time Frame: Days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part B, Cohort 4 [ Time Frame: Days 1: pre-dose, 1, 4, 24, 48 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: Observed Maximum Concentration Following Drug Administration (Cmax) in Part B, Cohort 5 [ Time Frame: Days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part B, Cohort 4 [ Time Frame: Days 1: pre-dose, 1, 4, 24, 48 hours post-dose ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: Time to Reach the Maximum Concentration After Drug Administration (Tmax) in Part B, Cohort 5 [ Time Frame: Days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) in Part B, Cohort 5 [ Time Frame: Day 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857:The Area Under the Plasma Concentration-time Curve From Zero to 48 Hours (AUC0_48h) in Part B, Cohort 4 [ Time Frame: Days 1: pre-dose, 1, 4, 24, 48 hours post-dose ]
    Serum samples were obtained for the PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857:The Area Under the Plasma Concentration-time Curve From Zero to 48 Hours (AUC0_48h) in Part B, Cohort 5 [ Time Frame: Days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. ]
  • Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) [ Time Frame: Part A: days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: The Terminal Elimination Half-life (T1/2) [ Time Frame: Part A: days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. ]
    Serum samples were obtained for PK assessment.
  • Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) [ Time Frame: Part A: days 1, 15, 29, 43: pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. Day 57: pre-dose, 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36: pre-dose, 1, 4, 24, 48 hours post-dose. Day 78: pre-dose, 1, 4, 24, 48, 168 hours post-dose. ]
    Serum samples were obtained for PK assessment.
  • Compare Dose Normalized Log-transformed AUCinf Following IV and SC Administrations [ Time Frame: In Part A: days 1 and 15, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. ]
    Serum samples were obtained for PK assessment.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 29, 2013)
  • Change in score on the adult myopathy assessment tool. [ Time Frame: Baseline and Day 85 in Part B. ]
  • Change in lean body mass. [ Time Frame: Baseline and Day 85 in Part B. ]
  • Plasma Pharmacokinetics (PK) of BVS857: Observed maximum concentration following drug administration (Cmax) [ Time Frame: Part A: days 1, 15, 29, 43, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. On day 57, pre-dose. 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36, pre-dose, 4, 24, 48 hours post-dose. On day 78, pre-dose, 4, 24, 48, 168 hours post-dose. ]
  • Plasma Pharmacokinetics (PK) of BVS857: Time to reach the maximum concentration after drug administration (Tmax) [ Time Frame: Part A: days 1, 15, 29, 43, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. On day 57, pre-dose. 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36, pre-dose, 4, 24, 48 hours post-dose. On day 78, pre-dose, 4, 24, 48, 168 hours post-dose. ]
  • Plasma Pharmacokinetics (PK) of BVS857: The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) [ Time Frame: Part A: days 1, 15, 29, 43, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. On day 57, pre-dose. 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36, pre-dose, 4, 24, 48 hours post-dose. On day 78, pre-dose, 4, 24, 48, 168 hours post-dose. ]
  • Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) [ Time Frame: Part A: days 1, 15, 29, 43, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. On day 57, pre-dose. 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36, pre-dose, 4, 24, 48 hours post-dose. On day 78, pre-dose, 4, 24, 48, 168 hours post-dose. ]
  • Plasma Pharmacokinetics (PK) of BVS857: The Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) [ Time Frame: Part A: days 1, 15, 29, 43, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. On day 57, pre-dose. 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36, pre-dose, 4, 24, 48 hours post-dose. On day 78, pre-dose, 4, 24, 48, 168 hours post-dose. ]
  • Plasma Pharmacokinetics (PK) of BVS857: The Terminal Elimination Half-life (T1/2) [ Time Frame: Part A: days 1, 15, 29, 43, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. On day 57, pre-dose. 1, 4, 12, 24, 48, 168, 504 hours post-dose. Part B: days 1 and 36, pre-dose, 4, 24, 48 hours post-dose. On day 78, pre-dose, 4, 24, 48, 168 hours post-dose. ]
  • Compare dose normalized log-transformed AUCinf following IV and SC administrations. [ Time Frame: In Part A: days 1 and 15, pre-dose, 1, 4, 12, 24, 48, 168 hours post-dose. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, and Efficacy of BVS857 in Patients With Spinal and Bulbar Muscular Atrophy
Official Title  ICMJE A Two-part Placebo-controlled Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of BVS857 in Patients With Spinal and Bulbar Muscular Atrophy (SBMA)
Brief Summary The purpose of this study was to determine if BVS857 is safe, tolerable and increases thigh muscle thickness in patients with spinal bulbar and muscular atrophy (SBMA).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Spinal and Bulbar Muscular Atrophy
Intervention  ICMJE
  • Drug: BVS857
    BVS857 lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..
  • Drug: Placebo
    Placebo lyophilisate in vial; the lyophilisate was reconstituted with sterile water for injection, diluted as appropriate, and administered either i.v. or s.c..
Study Arms  ICMJE
  • Experimental: BVS857 Part A Open label (Cohort 1)
    Participants received single doses of 0.01 mg/kg BVS857 intravenously (i.v.) on day 1, 0.01 mg/kg BVS857 subcutaneously (s.c.) on day 15, 0.03 mg/kg BVS857 s.c. on day 29, 0.06 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57.
    Intervention: Drug: BVS857
  • Experimental: BVS857 Part A double blind (Cohort 2)
    Participants received single doses of 0.03 mg/kg BVS857 i.v on day 1, 0.03 mg/kg BVS857 s.c. on day 15, 0.06 mg/kg BVS857 s.c. on day 29, 0.10 mg/kg BVS857 s.c. on day 43 and 0.10 mg/kg BVS857 s.c. on day 57. (BVS857 concentrations differed on days 43 and 57.)
    Intervention: Drug: BVS857
  • Placebo Comparator: Placebo Part A double blind (Cohort 2)
    Participants received single doses of matching placebo i.v. on day 1 and matching placebo s.c. on days 15, 29, 43 and 57.
    Intervention: Drug: Placebo
  • Experimental: BVS857 Part B open-label (Cohort 4)
    Participants received 0.1 mg/kg BVS857 i.v. weekly for 12 weeks.
    Intervention: Drug: BVS857
  • Experimental: BVS857 Part B double blind (Cohort 5)
    Participants received 0.06 mg/kg (maximum 6 mg) BVS857 i.v. weekly for 12 weeks.
    Intervention: Drug: BVS857
  • Placebo Comparator: Placebo Part B double blind (Cohort 5)
    Participants received matching placebo i.v. to BVS857 weekly for 12 weeks.
    Intervention: Drug: Placebo
Publications * Grunseich C, Miller R, Swan T, Glass DJ, El Mouelhi M, Fornaro M, Petricoul O, Vostiar I, Roubenoff R, Meriggioli MN, Kokkinis A, Guber RD, Budron MS, Vissing J, Soraru G, Mozaffar T, Ludolph A, Kissel JT, Fischbeck KH; BVS857 study group. Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial. Lancet Neurol. 2018 Dec;17(12):1043-1052. doi: 10.1016/S1474-4422(18)30320-X. Epub 2018 Oct 15.

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: May 5, 2016)
37
Original Estimated Enrollment  ICMJE
 (submitted: December 29, 2013)
38
Actual Study Completion Date  ICMJE April 13, 2016
Actual Primary Completion Date April 13, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • Genetic diagnosis of SBMA with symptomatic muscle weakness
  • Able to complete 2 minute timed walk
  • Serum IGF-1 level less than or equal to 170 ng/mL

Key Exclusion Criteria:

  • Medically treated diabetes mellitus or known history of hypoglycemia
  • History of Bell's palsy
  • Treatment with systemic steroids > 10 mg/day (or equivalent dose); androgens or androgen reducing agents; systemic beta agonists; or other muscle anabolic drugs within the previous 3 months
  • History of cancer, other than non-melanomatous skin cancer
  • Retinopathy
  • Papilledema Other protocol defined inclusion/exclusion criteria may apply
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark,   Germany,   Italy,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02024932
Other Study ID Numbers  ICMJE CBVS857X2202
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date March 2019

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