A Proof-of-Mechanism Study to Determine the Effect of ACH-0144471 on C3 Levels in Patients With C3G or IC-MPGN

• ClinicalTrials.gov Identifier: NCT03124368
• Recruitment Status: Completed
• First Posted: April 21, 2017
• Last Update Posted: November 7, 2019
• Sponsor: Alexion Pharmaceuticals
• Information provided by (Responsible Party): Alexion Pharmaceuticals

Study Description

Brief Summary:

The primary objective of this study is to determine whether ACH-0144471 can increase blood C3 levels in participants with low C3 levels due to either C3G or IC-MPGN.

Condition or disease	Intervention/treatment	Phase
C3 Glomerulonephritis; Dense Deposit Disease; Membranoproliferative Glomerulonephritis, Type II; C3 Glomerulopathy; Immune Complex Mediated Membranoproliferative Glomerulonephritis	Drug: ACH-0144471	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Phase 2a Proof-of-Mechanism, Open-Label Study to Determine the Effect of ACH-0144471 on C3 Levels in Patients With Low C3 Levels Due to Either C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN)
• Actual Study Start Date: August 9, 2017
• Actual Primary Completion Date: December 21, 2018
• Actual Study Completion Date: January 8, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sentinel Group 1; All participants will receive ACH-0144471 during the treatment period.	Drug: ACH-0144471; Participants will receive study drug for 14 days (Treatment Period), followed by a taper over the next 7 days (Taper Period); Other Names: ACH-4471; ACH4471; 4471
Experimental: Group 2; All participants will receive ACH-0144471 during the treatment period.	Drug: ACH-0144471; Participants will receive study drug for 14 days (Treatment Period), followed by a taper over the next 7 days (Taper Period); Other Names: ACH-4471; ACH4471; 4471

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Blood C3 levels at Day 14 [ Time Frame: Baseline, Day 14 ]

Secondary Outcome Measures :

1. Serious Adverse Events (SAEs), Grade 3 or Higher Adverse Events (AEs), and AEs Leading to Discontinuation [ Time Frame: up to Day 49 ]
2. Time (in Days) to Achieving Peak C3 Levels From the First Day of Dosing [ Time Frame: Day 14 ]
3. Pharmacokinetics: Area Under the Curve (AUC) [ Time Frame: Days 1 & 7 ]
4. Pharmacokinetics: Maximum Plasma Concentration (Cmax) [ Time Frame: Days 1 & 7 ]
5. Profile of Pharmacokinetics: Time to maximum concentration (Tmax) [ Time Frame: Days 1 & 7 ]
6. Change from Baseline in Biomarkers of Alternative Pathway (AP) activity (AP Wieslab, factor D, and Bb) [ Time Frame: Baseline, Day 14 ]
7. Relationship between ACH-0144471 exposure and changes in C3 levels and other biomarkers of alternative pathway activity (AP Wieslab, factor D, and Bb) [ Time Frame: Day 14 ]

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Must have a clinical diagnosis of C3G (C3 glomerulonephritis [C3GN] or dense deposit disease [DDD], the 2 types of C3G) or idiopathic immune-complex membranoproliferative glomerulonephritis (IC-MPGN) by renal biopsy for at least 3 months prior to dosing, with the pathologic diagnosis verified by review of the renal biopsy by the study central pathologist
• C3 must be <50% of the lower limit of normal
• C4 must be >90% of the lower limit of normal
• Must be willing to comply with study-specific vaccination requirements for Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis strains A, C, W, and Y
• Negative pregnancy test for females prior to dosing and throughout the study

Exclusion Criteria:

• History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. Individuals receiving renal replacement therapy are also excluded
• Evidence of monoclonal gammopathy of unclear significance (MGUS), infections, malignancy, autoimmune diseases, or other conditions to which C3 glomerulopathy or IC-MPGN may be secondary
• Estimated glomerular filtration rate (eGFR; using MDRD equation) <45 mL/min/1.73 m2 at the time of screening or at any time over the preceding four-weeks
• Receipt of eculizumab at any dose or interval within the past 75 days prior to dosing
• Use of tacrolimus or cyclosporine within 2 weeks of the first dose of ACH-0144471
• History of febrile illness, a body temperature >38°C, or other evidence of a clinically significant active infection, within 14 days prior to study drug administration
• History of meningococcal infection, or a first-degree relative or household contact with a history of meningococcal infection
• Females who are pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration or patients with a female partner who is pregnant, nursing, or planning to become pregnant during the study or within 90 days of study drug administration

NOTE: Additional inclusion/exclusion criteria may apply, per protocol.

Contacts and Locations

Locations

Australia

The Royal Melbourne Hospital

Melbourne, Australia

Belgium

ZNA Middelheim

Antwerpen, Belgium

Netherlands

Leiden University

Leiden, Netherlands

Amalia Children's Hospital

Nijmegen, Netherlands

Radboud University Nijmegen Medical Centre

Nijmegen, Netherlands

Sponsors and Collaborators

Alexion Pharmaceuticals

More Information

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03124368
• Other Study ID Numbers: ACH471-201; 2016-003525-42 ( EudraCT Number )
• First Posted: April 21, 2017
• Last Update Posted: November 7, 2019
• Last Verified: November 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Alexion Pharmaceuticals:

factor D; fD; alternative pathway; complement mediated disease; idiopathic MPGN; MPGN Type I; MPGN Type II; MPGN Type III; Primary MPGN; MCGN; Mesangiocapillary Glomerulonephritis

Additional relevant MeSH terms:

Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Nephritis; Kidney Diseases; Urologic Diseases; Immune System Diseases