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

• ClinicalTrials.gov Identifier: NCT02024932
• Recruitment Status: Completed
• First Posted: December 31, 2013
• Results First Posted: August 11, 2017
• Last Update Posted: January 5, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: December 29, 2013
• First Posted Date: December 31, 2013
• Results First Submitted Date: April 12, 2017
• Results First Posted Date: August 11, 2017
• Last Update Posted Date: January 5, 2021
• Actual Study Start Date: February 4, 2014
• Actual Primary Completion Date: April 13, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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. ]

Current Secondary Outcome Measures (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 (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: Safety, Tolerability, and Efficacy of BVS857 in Patients With Spinal and Bulbar Muscular Atrophy
• Official Title: 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Spinal and Bulbar Muscular Atrophy

Intervention

• 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

• 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.

Recruitment Information

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

Eligibility Criteria

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

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark, Germany, Italy, United States

Administrative Information

• NCT Number: NCT02024932
• Other Study ID Numbers: CBVS857X2202
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: March 2019