Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06258850 |
| Other study ID # |
ICI23/00001 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2024 |
| Est. completion date |
December 2027 |
Study information
| Verified date |
February 2024 |
| Source |
Parc de Salut Mar |
| Contact |
Diego A Rodríguez Chiaradía, MD PhD |
| Phone |
+34922483548 |
| Email |
darodriguez[@]psmar.cat |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Background. Pulmonary arterial hypertension (PAH) is a heterogeneous pathophysiological
condition characterized by progressive pulmonary vascular narrowing that ultimately results
in right-sided heart failure and eventually death or lung transplantation. The effectiveness
of current pharmacological treatments is suboptimal and a large proportion of patients still
had events or died despite receiving combination therapy. Vitamin D deficiency has been found
to be much more frequent in PAH patients than in the general population or even compared to
patients with other severe cardiovascular diseases. Moreover, vitamin D deficiency has a
negative prognostic impact in PAH. Animal studies support that vitamin D deficiency worsens
PAH.
Hypothesis. In patients with PAH and vitamin D deficiency, restoration of vitamin D status
with calcifediol improves their symptomatology and prognosis.
Design: Multicenter clinical trial with the participation of 9 hospitals, placebo-controlled,
randomized (1:1 ratio), in two parallel groups (without crossover), triple blind, and add-on
on existing treatments (add-on). It will include at least 102 subjects (51 in the calcifediol
group and 51 in the placebo group) followed for 24 weeks of treatment.
Inclusion criteria: Patients of both sexes (18-75 years) with hemodynamic diagnosis of PAH
and severe vitamin D deficiency (25-OHvitD <= 12 ng/ml) and without previous diagnosis of
osteoporosis or osteomalacia.
Treatments: 1) Calcifediol Hydroferol® 0.266 mg once every 10 days for the first 12 weeks and
once every two weeks for the following 12 weeks. 2) Placebo.
Main objective: A composite endpoint of clinical improvement without clinical worsening at
week 24.
Expected outcome: Restoration of vitamin D status is an unexpensive measure, very easily
implantable and that could improve the evolution of the disease as well as other aspects such
as bone or immune health and that has few side effects.
Description:
RESEARCH TEAM PI: Diego A. Rodríguez Chiaradía, Co-PI: Francisco Perez-Vizcaino.
Investigators: Joan A. Barberá, Isabel Blanco Vich, Manuel Lopez Meseguer, Amaya Martinez
Menaca, Gregorio M Perez Peñate, Raquel López Reyes, Alberto García Ortega, Jose Andres
Tenes, Remedios Otero.
RATIONALE: There is no evidence to support that there is a causal link, at least in humans,
between vitamin D deficiency and PAH. Moreover, if present, the causal relationship might be
in either direction: vitamin D causing/aggravating PAH or PAH inducing vitamin D deficiency.
Only data from preclinical or small uncontrolled trials are available that suggest that low
vitamin D aggravates PH. Thus, the key clinical question for PAH patients that we are
addressing herein is: Does restoration of vitamin D levels lead to clinical improvement and
better prognosis in PAH patients?
Thus, our HYPOTHESIS is that in patients with stable PAH and vitamin D deficiency,
restoration of the vitamin D status with calcifediol supplements improves symptoms and
prognosis.
MAIN OBJECTIVE. To analyze whether a vitamin D supplement (0,266 mg calcifediol, once every
10 days for the first 12 weeks and once every second week in the following 12 weeks) induces
clinical improvement without clinical worsening at week 24 compared with placebo.
DISEASE. The study will be performed in patients with PAH and severe deficit of vitamin D.
Patients will be at intermediate risk of 1-year mortality according to 2022 European
Respiratory Society /European Society of Cardiology guidelines despite receiving standard
treatment for PAH for at least 6 weeks before randomisation.
CLINICAL PHASE. Phase IV clinical trial analyzing the therapeutic effects, as measured by a
composite endpoint of morbidity and mortality, of a commercial source of vitamin D
(Hidroferol® 0,266 mg) available in Spain.
PARTICIPATING CENTERS. This is a multicentric study that will be conducted in 9
hospital-based pulmonary hypertension centres in Spain.
ETHICS AND PATIENT CONSENT. The institutional review board at each participating centre will
approve the protocol, and the study will be carried out in accordance with Good Clinical
Practice guidelines and the Declaration of Helsinki. All patients will provide written
informed consent.
STUDY DESIGN. Multicentric, randomized, placebo controlled (1:1 proportion), quadruple blind,
parallel, add-on, superiority trial.
EXPERIMENTAL DRUG AND ROUTE OF ADMINISTRATION. Patients in the active arm will receive oral
calcifediol (25-OH vitamin D3) or placebo.
DOSING: One Hydroferol® soft capsule (0.266 mg) or one placebo capsule will be administered
once every 10 days for the first 12 weeks and one capsule every two weeks for the next 12
weeks.
ADD-ON. At randomization patients must be treated with the standard care including the
specific drugs for PAH according to ERS/ESC guidelines and stable for at least 6 weeks.
Patients will start the active or placebo treatment and remain with their current PAH
treatments.
STUDY POPULATION: Patients of both sexes and ages between 18 years and 75 years with a
diagnosis of PAH and severe vitamin D deficiency.
PATIENT RECRUITMENT. Patients with a previous diagnosis of PAH, stable for the 6 weeks, that
regularly attend the PH patient outclinic of the participating hospitals will be recruited.
DIAGNOSIS of PAH. PAH diagnosis according to the 2022 European Society of Cardiology/European
Respiratory Society guidelines must have been performed in an accredited PH reference unit.
Therefore, patients must present precapillary PH with hemodynamic parameters, measured by
right heart catheterization, of mPAP >20 mmHg, pulmonary artery wedge pressure (PAWP) ≤15
mmHg and pulmonary vascular resistance (PVR) >2 WU)] in the absence of other causes of
pre-capillary PH, such as chronic thromboembolic PH and PH associated with lung diseases.
DEFINITION OF SEVERE VITAMIN D DEFICIENCY. The best biomarker of vitamin D status is the
serum or plasma level of the hydroxylated form or vitamin D, 25(OH)-cholecalciferol, also
known as 25(OH)-vitamin D or calcifediol. Although there is no universal consensus on its
optimal levels or those representing insufficiency or deficiency, most scientific societies
and regulatory agencies define vitamin D deficiency as serum or plasma levels of
25(OH)-vitamin D below 20 ng/ml. According to this, ninety-five percent of the patients with
PAH in the Spanish cohort showed vitamin D deficiency. However, patients with the lowest
values showed poorer prognosis, suggesting that there are important differences depending on
the severity of the deficit. Therefore, patients with the most severe deficiency are expected
to be those obtaining greatest benefit. There is no widely accepted definition of severe
deficiency. Herein, we will define severe vitamin D deficiency as serum 25(OH)-vitamin D
levels equal to or less than 12 ng/ml. According to this definition and the data of the
Spanish PAH cohort, we expect that ~75% of the otherwise eligible PAH patients will fit into
this category. This arbitrary cutoff value intends to recruit a large percentage of patients
that are expected to have the maximal benefit. Therefore, patients with values of 12-20 ng/ml
that would potentially obtain marginal benefit will be excluded.
RANDOMIZATION. Patients will be randomized 1:1 to placebo (the control arm) or to Hidroferol
(active arm). A randomization list will be generated using the SAS 9 software for Windows.
The randomization list will be imported into the REDCap program so that researchers can
randomize candidate subjects using a more user-friendly interface. Subjects who meet the
selection criteria will be randomized between treatment groups, in order to achieve balanced
randomization in treatment groups. The treatment assignment will be centralized, thus keeping
the sequence hidden.
BLINDING AND MASKING. Placebo capsules will be identical to those of the active treatment.
The batch of capsules for each patient will be codified and codes will be provided by the
producing company to the SCReN platform who will keep them so that patients and
investigators, the local pharmacy will be blind.
MAIN VARIABLES OF THE STUDY. Baseline and 6-month values of the following variables will be
compared and be used either for the composite endpoint or as secondary objectives: a) 6MWD,
b) serum pro-BNP, c) functional class (WHO/NYAS), d) noninvasive risk score (NIRS) based on
the three previous variables, e) ventricular function analyzed echocardiographically by TAPSE
and f) a mechanistic parameter: serum noggin levels (difference: at 6 months minus baseline).
In addition, quality of life will be compared using the emPHasis-10 questionnaire.
Echo-doppler will be performed at each hospital and the images will be centrally and blindly
analyzed by a single expert echocardiographer.
VISITS. Visit 0 (-2 to -4 weeks): Informed consent and eligibility criteria, 6MWD, functional
class and blood sampling for 25(OH) vitamin D and NT-proBNP. Visit 1 (week 0): Randomization.
Visit 2 (week 12): Safety analysis of 25(OH)vitamin D and calcium levels. Visit 3 (week 24):
analysis of efficacy. Central phone calls at week 2, 4, 10 and 20 will be made to assess
compliance and possible adverse effects.
WITHDRAWAL OF PATIENTS FROM THE STUDY. Patients must be withdrawn from study treatment: 1) at
their own request, 2) when in the investigator's opinion, continuation of the study treatment
would be harmful to the patient's well-being. 3) Occurrence of adverse events (AEs) or
intercurrent diseases which the investigator judges unacceptable for continuation of
participation in the study. 4) Occurrence of adverse drug reactions, which have from the
investigator's point of view, a negative impact on the patient's individual risk-benefit
ratio. 5) Pertinent noncompliance with the conditions for the study or instructions by the
investigator 6) In case of pregnancy or breast feeding 7) Participation in another clinical
study, 8) Patient does not tolerate the experimental drug. 9) Patients in the active arm with
25 (OH) vitamin D levels below 20 ng/ml or above 100 ng/ml and patients in the placebo arm
with values above 20 ng/ml in the intermediate safety analysis.
RISKS. Adverse reactions of hydroferol® are generally uncommon (> 1/1,000 to < 1/100)
although they are sometimes moderately important. The most significant adverse effects are
related to excessive intake of vitamin D, especially when associated with high doses of
calcium, which is not the case per study protocol. The most characteristic adverse reactions
are due to the hypercalcaemia.
INTERMEDIATE SAFETY ANALYSIS. Serum 25(OH)vitamin D will be centrally analyzed in patients
receiving either the active treatment or placebo at 12 weeks. The results will be
communicated neither to patients nor investigators except for the following cases. Patients
in the active arm with 25(OH) vitamin D levels below 20 ng/ml or above 100 ng/ml or with
hypercalcemia and patients in the placebo arm with values above 20 ng/ml will be discontinued
from the study.
STATISTICAL ANALYSIS Sample size. Calculations for the present project are based mainly in
the REPLACE trial (PMID: 33773120). The main endpoint in both trials is similar except that
clinical improvement is based on two out of four variables (now includes TAPSE/PASP) instead
of two out of three. We expect that this would lead to an increase in events of 25% in both
arms. We assume that our placebo group is similar to the REPLACE control group and we expect
that the vitamin D group would lead to a clinical improvement similar to that of the
riociguat group in REPLACE. The rate of clinical improvement without clinical worsening at
week 24 was estimated to be 50% for the vitamin D group and 25% for the placebo. A sample
size of 51 patients per arm was calculated using granmo® software (with two-sample frequency,
X² test, one-sided alpha=0.05, power=0.8) with an estimated dropout rate of 10%.
Outcomes. All analyses will be performed using the program applied to the SAS statistics,
version 9 of the SAS system for Windows. At the end of the study, summaries of the
demographic variables and other characteristics of the subjects specified in the data
collection notebook will be made according to the two treatment groups. Unless otherwise
specified, all continuous variables shall be summarized using number of patients (n), mean,
standard deviation, median, minimum, and maximum. Categorical variables shall be described by
absolute and relative frequency. The statistical analysis plan (SAP) will be developed and
finalized prior to the publication of the database and will describe the populations of
subjects to be included in the analyses and the procedures for accounting for missing, unused
and non-essential data. Comparisons between groups will be made using one-sided Fisher's
exact test. Likewise, a multivariate analysis of the main outcome will be made using a binary
logistic regression analysis. Changes on detailed parameters on secondary objectives, will be
analyzed through suitable methods for repeated measures (paired t test or equivalent
non-parametric Wilcoxon Rank-Sum test). Also, between group differences, will be performed
comparing 24 week vs. baseline differences by group. This will be checked through t test or
Mann-Whitney test depending on the results of the normality tests in the continuous
variables. Finally, repeated measures ANCOVA will be applied to check effects of possible
confounding variables.
Data Management Plan. All the data of the participants related to the study will be recorded
in an Electronic Data Collection (EDC) whose preparation and maintenance will be carried out
from the ISCIII Support Platform for Clinical Research (SCReN).
