This study has been transitioned to CTIS with ID 2023-509331-83-00 check the CTIS register for the current data. Primary objective adults:To demonstrate the superiority of iptacopan (200 mg b.i.d.) compared to placebo in reducing proteinuria at 6…
ID
Source
Brief title
Condition
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
In adults and adolescents:
• Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine
collection) at 6 months.
In adults and adolescents Open Label phase:
• Change from baseline in log-transformed UPCR at the 12-month visit (both
study treatment arms).
• Change in log-transformed UPCR from the 6-month visit to the 12-month visit
in the placebo arm.
Secondary outcome
In adults:
• Change from baseline in eGFR at 6 months.
• A participant meets the requirements of the composite renal endpoint if
he/she satisfies the following criteria at the 6-month time point: (1) a stable
or improved eGFR compared to the baseline visit (<=15% reduction in eGFR), and
(2) a >=50% reduction in UPCR compared to the baseline visit. Initiation of
treatment with any complement pathway modifying agent or
initiation/intensification of corticosteroid or immunosuppressant or renal
replacement therapy automatically designates the participant as not meeting the
endpoint.
• Change from baseline in disease total activity score in a renal biopsy at 6
months.
• Change from baseline to 6 months in the Functional Assessment of Chronic
Illness Therapy-Fatigue (FACIT-Fatigue) score.
• Occurrence of clinically significant vital signs (msDBP, msSBP, heart rate),
ECGs, and safety laboratory measurements, as well as adverse events (AEs), AEs
of special interest, and study drug discontinuation due to an AE (or any safety
issue) during the double-blind period of the study.
In adolescents:
• Change from baseline in eGFR at 6 months.
• A participant meets the requirements of the composite renal endpoint if
he/she satisfies the following criteria at the 6-month time point: (1) a stable
or improved eGFR compared to the baseline visit (<=15% reduction in eGFR), and
(2) a >=50% reduction in UPCR compared to the baseline visit. Initiation of
treatment with any complement pathway modifying agent or
initiation/intensification of corticosteroid or immunosuppressant or renal
replacement therapy automatically designates the participant as not meeting the
endpoint.
• Change from baseline to 6 months in the Functional Assessment of Chronic
Illness Therapy-Fatigue (FACIT-Fatigue) score.
• Occurrence of clinically significant vital signs (msDBP, msSBP, heart rate),
ECGs, and safety laboratory measurements, as well as adverse events (AEs), AEs
of special interest, and study drug discontinuation due to an AE (or any safety
issue) during the double-blind period of the study.
• Evaluation of iptacopan*s potential effects on heart rate, systolic and
diastolic blood pressures, cardiac function and a cardiac biomarker throughout
the double-blind and open- label treatment periods.
Open Label phase adults and adolescents:
• A participant is defined as meeting the requirements of the composite renal
endpoint if they satisfy the eGFR and UPCR criteria at the 12-month time point
(both treatment arms).
The rate of this endpoint will also be evaluated in the placebo arm at the
12-month visit compared to the 6-month visit.
• Only adults: Change from baseline in the total activity score in a renal
biopsy at 12 months (both study treatment arms).
Change in the total activity score in a renal biopsy from the 6-month visit to
the 12-month visit of the placebo arm.
• Change from baseline in the FACIT-Fatigue score at 12 months (both study
treatment arms).
Change in the FACIT-Fatigue score from the 6-month visit to the 12-month visit
of the placebo arm.
• Occurrence of clinically significant vital signs (msDBP, msSBP, heart rate),
ECGs, and safety laboratory measurements, as well as adverse events (AEs), AEs
of special interest, and study drug discontinuation due to an AE (or any safety
issue) during the open-label period of the study (and combined with the
double-blind period).
Background summary
The purpose of this Phase 3 study is to evaluate the efficacy and safety of
iptacopan compared to placebo (and standard of care) in patients (adults and
adolescents) with native C3G. Adult and adolescent participants will be
randomized independently and separate analyses will be conducted in the adult
and adolescent cohorts. The study aims to demostrate a reduction in proteinuria
and improvement in estimated Glomerular Filtration Rate (eGFR) in participants
treated with iptacopan compared to placebo. Kidney biopsies will be performed
in adults only to assess histopathological reductions in glomerular
inflammation and Complement 3 (C3) deposition, and improvement in fatigue will
be evaluated. Complement alternative pathway (AP) dysregulation is believed to
underlie the clinical manifestations and progression of C3G. Serum C3 and other
complement pathway biomakers will be assessed to demonstrate that ipatacopan
reduces AP activity and targets the underlying cause of disease.
Study objective
This study has been transitioned to CTIS with ID 2023-509331-83-00 check the CTIS register for the current data.
Primary objective adults:
To demonstrate the superiority of iptacopan (200 mg b.i.d.) compared to placebo
in reducing proteinuria at 6 months of treatment.
The primary clinical question of interest is:
What is the effect of iptacopan vs. placebo on log-transformed ratio to
baseline in urinary protein/creatinine ratio (UPCR, sampledfrom a 24-hour urine
collection) at 6 months.
Primary objective adolescents:
To evaluate the effect of iptacopan on proteinuria at 6 months treatment.
Primary objective open-label treatment period adults and adolescents:
To evaluate the effect of iptacopan on proteinuria at 12 months.
Secundary objective adults:
To demonstrate the superiority of iptacopan vs. placebo in improving eGFR by
assessing the change from baseline in eGFR at 6months.
To demonstrate the superiority of iptacopan vs. placebo in the proportion of
participants who achieved the composite renal endpoint.A participant meets the
requirements of the composite renal endpoint if he/she satisfies the following
criteria at the 6-month timepoint: (1) a stable or improved eGFR compared to
the baseline visit (<=15% reduction in eGFR), and (2) a >=50% reduction in
UPCRcompared to the baseline visit. Initiation of treatment with any complement
pathway modifying agent or initiation/intensification ofcorticosteroids or
immunosuppressants or renal replacement therapy automatically designates the
participant as not having met theendpoint.
To demonstrate the effect of iptacopan vs placebo in reducing glomerular
inflammation in the kidney by assessing the change frombaseline in disease
total activity score in a renal biopsy at 6 months.
To assess the effect of iptacopan compared to placebo in improvement of
patient-reported fatigue by assessing the change frombaseline to 6 months in
the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)
score.
To evaluate the safety and tolerability of iptacopan compared to placebo during
the 6-month double-blind period by assessing theoccurrence of clinically
significant vital signs, Electrocardiograms (ECGs), and safety laboratory
measurements, as well as adverseevents (AEs), AEs of special interest, and
study drug discontinuation due to an AE (or any safety issue) during the
double-blindportion of the study.
Secundary objective adolescents:
To evaluate the effect of iptacopan in improving eGFR by assessing the change
from baseline in eGFR at 6 months.
To evaluate the effect of iptacopan on a composite renal endpoint. A
participant meets the requirements of the composite renal endpoint if he/she
satisfies the following criteria at the 6-month time point: (1) a stable or
improved eGFR compared to the baseline visit (<=15% reduction in eGFR), and (2)
a >=50% reduction in UPCR compared to the baseline visit. Initiation of
treatment with any complement pathway modifying agent or
initiation/intensification of corticosteroids or immunosuppressants or renal
replacement therapy automatically designates the participant as not having met
the endpoint.
To evaluate the effect of iptacopan in improvement of patient-reported fatigue
by assessing the change from baseline to 6 months in the Functional Assessment
of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score.
To evaluate the safety and tolerability of iptacopan compared to placebo during
the 6-month double-blind period by assessing the occurrence of clinically
significant vital signs, Electrocardiograms (ECGs), and safety laboratory
measurements, as well as adverse events (AEs), AEs of special interest, and
study drug discontinuation due to an AE (or any safety issue) during the
double-blind portion of the study.
Additional CV safety surveillance: the evaluation of iptacopan*s potential
effects on heart rate, systolic and diastolic blood pressures, cardiac function
and a cardiac biomarker throughout the double-blind and open- label treatment
periods.
Secundary objective open-label treatment period adults and adolescents:
To evaluate the effect at 12 months of iptacopan on a composite renal endpoint,
in reducing glomerular inflammation in the kidney and in improvement of patient
reported fatigue.
To evaluate the safety and tolerability of iptacopan during the 6-month
open-label treatment period as well as the entire 12-month treatment period.
Study design
This study is a multicenter, randomized, double-blind, parallel group,
placebo-controlled study to evaluate the efficacy and safety of iptacopan in
patients with native C3G. Approximately 68 adult and 15 adolescent participants
will be randomized in the trial (adult and adolescent cohorts will be analyzed
separately). Half of the adult participants (n=34) will receive iptacopan at
200 mg b.i.d. as blinded treatment for 6 months followed by 6 months of
open-label iptacopan at 200 mg b.i.d. The other half of participants (n=34)
will receive placebo as blinded treatment for 6 months followed by 6 months of
open-label iptacopan at 200 mg b.i.d. Adolescent participants will be
randomized 2:1 with approximately 10 receiving iptacopan at 200 mg b.i.d. as
blinded treatment for 6 months followed by 6 months of open-label iptacopan at
200 mg b.i.d. The other approximately 5 participants will receive placebo as
blinded treatment for 6 months followed by 6 months of open-label iptacopan at
200 mg b.i.d. Upon completion of study treatment at 12 months, participants
will have the option to discontinue iptacopan treatment and enter a Safety
Follow-up period or continue open-label iptacopan treatment by transitioning to
a C3G Extension study.
Intervention
Adult participants will be randomized to one of the two treatment arms in a 1:1
ratio.
• Iptacopan arm: Iptacopan orally at 200 mg b.i.d. for 6 months (double-blind)
followed by open-label iptacopan at 200 mg b.i.d. for an additional 6 months
• Placebo arm: Placebo orally for 6 months (double-blind) followed by
open-label iptacopan at 200 mg b.i.d. for an additional 6 months
Asolescent participants will be randomized to one of the two treatment arms in
a 2:1 ratio.
• Iptacopan arm: Iptacopan orally at 200 mg b.i.d. for 6 months (double-blind)
followed by open-label iptacopan at 200 mg b.i.d. for an additional 6 months
• Placebo arm: Placebo orally for 6 months (double-blind) followed by
open-label iptacopan at 200 mg b.i.d. for an additional 6 months
Study burden and risks
Infections due to the effect of LNP023 on the immune system
Delayed maturation of sperm, not observed in humans to date
Damage to the bone marrow and anemia, not observed in humans at lower doses
Thyroid disorders, so far not observed in humans
Cardiac effects: hemodynamic and long term morphological changes (observed only
in juvenile dog toxicity studies
Vaccination 1-3x against Neisseria meningitidis, Streptococcus pneumoniae and
Haemophilus influenzae
Physical examination 10x
Vital signs 10x
Blood and urine test 10x
24 hour urine collection 4x
Morning urine 10x
Kidney biopsy (adults only)
ECG 4x
Questionnaires 8x
Keep a diary: daily
Tanner puberty scale 2x (adolescents only)
7 hours cardiovascular surveillance 2x (adolescents only)
Echocardiography 5x (adolescents only)
Home (55x) and ambulant 24 hour monitoring (3x) of blood pressure and heart
rate (adolescents only)
Optional, additional exploratory capillair blood sampling 2x (adolescents only)
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
Male and female participants age >= 18 and <= 60 years (adult cohort) or age >= 12
and <=
17 years (adolescent cohort) at screening.
Diagnosis of C3G as confirmed by renal biopsy within 12 months prior to
enrollment in adults and within 3 years of enrollment in adolescents (a biopsy
report, review and confirmation by the Investigator is required). If such a
biopsy is not available, confirmation may be obtained using tissue from the Day
-45 biopsy (adults only) for local assessment (tissue may be processed,
evaluated, and reported by Arkana Laboratories but eligibility is determined by
the Investigator).
Prior to randomization, all participants must have been on a maximally
recommended or tolerated dose of an angiotensin converting enzyme inhibitor
(ACEI) or angiotensin receptor blocker (ARB) for at least 90 days. The doses of
other antiproteinuric medications including mycophenolic acids, corticosteroids
and mineralocorticoid receptor antagonists should be stable for at least 90
days prior to randomization.
Reduced serum C3 (defined as less than 0.85 x lower limit of the central
laboratory normal range) at Screening.
UPCR >= 1.0 g/g sampled from the first morning void urine sample at Day -75 and
Day -15.
Estimated GFR (using the CKD-EPI formula for adults and modified Schwartz
formula
for adolescents) or measured GFR >= 30 ml/min/1.73m2 at screening and Day -15.
Mandatory vaccination against Neisseria meningitidis and Streptococcus
Pneumoniae infection prior to the start of study treatment. If the patient has
not been previously vaccinated, or if a booster is required, the vaccine should
be given according to local regulations at least 2 weeks prior to the first
administration of study treatment. If study treatment has to start earlier than
2 weeks post vaccination, prophylactic antibiotic treatment should be initiated.
If not previously vaccinated, or if a booster is required, vaccination against
Haemophilus influenzae infections should be given, if available and according
to local regulations, at least 2 weeks prior to the first study treatment
administration. If study treatment has to start earlier than 2 weeks post
vaccination, prophylactic antibiotic treatment should be initiated.
Exclusion criteria
• Participants who have received any cell or organ transplantation, including
kidney transplantation. • Rapidly progressive crescentic glomerulonephritis
defined as a 50% decline in the eGFR within 3 months) with renal biopsy
findings of glomerular crescent formation seen in at least 50% of glomeruli. •
Renal biopsy showing interstitial fibrosis/tubular atrophy (IF/TA) of more than
50%. • Monoclonal gammopathy of undetermined significance (MGUS) confirmed by
the measurement of serum free light chains or other investigation as per local
standard of care. • Participants with an active systemic bacterial, viral or
fungal infection within 14 days prior to study treatment administration or the
presence of fever >= 38°C (100.4°F) within 7 days prior to study treatment
administration. • A history of recurrent invasive infections caused by
encapsulated organisms, e.g., meningococcus or pneumococcus. • The use of
inhibitors of complement factors (e.g., Factor B, Factor D, C3 inhibitors, anti
Complement 5 (C5) antibodies, C5a receptor antagonists) within 6 months prior
to the Screening visit. • The use of immunosuppressants (except mycophenolic
acids), cyclophosphamide or systemic corticosteroids at a dose >7.5 mg/day (or
equivalent for a similar medication) within 90 days of study drug
administration. The use of mycophenolic acids is not permitted within 90 days
prior to randomization in India. Acute post-infectious glomerulonephritis at
screening based upon the opinion of the Investigator.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-509331-83-00 |
| EudraCT | EUCTR2020-004589-21-NL |
| ClinicalTrials.gov | NCT04817618 |
| CCMO | NL77639.056.21 |