FARM12Y8HH_ARES

Fondazione Policlinico Gemelli

Largo A. Gemelli 1, Rome, Italy,

Area di ematologia, FONDAZIONE POLICLINICO GEMELLI, 0039 0630154968, valerio.destefano@policlinicogemelli.it

Area di ematologia, FONDAZIONE POLICLINICO GEMELLI, 0039 0630154968, valerio.destefano@policlinicogemelli.it

No

No

No

Final

23 Feb 2021

Yes

22 Feb 2021

Yes

31 Dec 2021

No

1- To investigate whether low-dose (100 mg) aspirin regimens twice or three times daily are superior to the standard once-daily regimen in inhibiting platelet-derived thromboxane (TX)A2, as assessed by the measurement of serum TXB2, without significantly affecting in vivo PGI2 biosynthesis, as assessed by its urinary metabolite (PGIM). The comparison between aspirin 100 mg twice or 3 times daily vs. 100 mg od was hypothesized and tested as a superiority hypothesis. PGIM comparisons was hypothesized and assess based on a non-inferiority hypothesis of any multiple daily dosing vs standard od regimen. 2- To evaluate the long-term persistence of superior biochemical efficacy of an optimized, multiple daily dosing regimen of aspirin, as compared to the standard 100 mg od regimen and its safety.

The Investigators conducted the study in compliance with the 2004 revision of the 1964 declaration of Helsinki and in accordance with Good Clinical Practice requirements described in the ICH guidelines included in the protocol. Prior to undergoing any study-specific procedure, all subjects gave their consent in writing to participate. The process of obtaining the informed consent was conducted in compliance with the Italian regulations. The ICF incorporated privacy working that complied with relevant data protection and privacy legislation. All possible measures to minimize pain and distress were adopted along the trial timeframe, although the IMP is a well-known drug with a known safety profile. Patients were prescribed proton pump inhibitors (PPI) according to current regulatory indications approved in Italy, when deemed necessary to reduce upper gastrointestinal symptoms. In case of occasional need of anti-inflammatory, antipyretic or analgesic drugs, patients were instructed to take paracetamol (up to 2000 mg daily) and avoid ibuprofen or naproxen of NSAIDs in general which have a known pharmacodynamic interaction with aspirin and may also potentiate its bleeding risk at the gastrointestinal level.

27 Jul 2017

No

Yes

Italy: 268

268

268

0

0

0

0

0

0

164

104

0

Run in

Non-randomised - controlled

acetylsalycilic acid

Tablet

Oral use

100 mg once daily

part A

Randomised - controlled

All patients had a 5-digit ID code which was sequential and not associated with the randomized arm, thus the laboratories measurements of the primary and secondary biomarker endpoints were performed by personnel who was blinded with regards of the randomized assignement. Patients were randomized to 3 arms in a 1:1:1 fashion: 100 mg of aspirin once, twice or three times daily with matching placebo tablets to achieve 3 tablet's intake per day.

Yes

acetylsalycilic acid

Tablet

Oral use

100 mg once daily

acetylsalycilic acid

Tablet

Oral use

100 mg twice daily

acetylsalycilic acid

Tablet

Oral use

100 mg three times daily

Part B

Randomised - controlled

Part B was open-label. However the laboratory measurements were performed by personnel who was blinded regarding the assigned randomized arm, since patients were sequentially identified with a 5-digit code.

acetylsalycilic acid

Tablet

Oral use

100 mg once daily

Run in

single arm

standard of care

twice daily

third daily

two arm protocol

Part A

251 eligible, aspirin-treated, consenting ET patients started the run-in phase, 6 patients withdrew their consent for personal reasons, 245 patients underwent randomization. There were no statistically significant differences of patient's characteristics across the 3 treatment arms. One patient assigned to aspirin 100 mg od exited the study for abdominal pain, and 1 patient had no serum sample available; 243 patients were evaluable and included in the analyses. Compliance: 218 out of 243 patients (90%) took all nine pills in the three days preceding visit 3 and were considered fully compliant. After two weeks of randomized aspirin treatment, serum TXB2 values of patients assigned to either the 100 mg bid or tid regimen were reduced by 80 to 90% versus their baseline values and were significantly lower than serum TXB2 values of patients assigned to 100 mg od.

Part B

242 aspirin-treated patients with essential thrombocythemia, were randomized to 100 mg aspirin twice- versus once-daily in addition to standard care. The primary endpoint was serum thromboxane B2, a biomarker of antithrombotic efficacy. On 10 visits during 20-month follow-up, serum thromboxane B2 was consistently lower in the twice-daily versus once-daily arm (median 3.9 ng/mL versus 19.2 ng/mL, respectively; P<0.001; median relative reduction 80%, 95% confidence interval, 74 to 85%). No major bleeding occurred. No statistically significant difference was found between the twice- and once-daily treatment groups regarding clinically relevant, non-major bleedings (6.6% versus 1.7%, p=ns), and major thromboses (0.8% versus 2.5%, p=ns ). Severe hand and foot microvascular pain was consistently less frequent in the twice-daily arm, while upper gastrointestinal pain scores were comparable in the two arms.

Part A and B: platelet thromboxane (TX)A2 production ex vivo, as reflected by serum TXB2 measured in samples collected in a fasting state, in the morning, before the next aspirin intake Part A: vascular PGI2 biosynthesis in vivo, as reflected by urinary 2,3-dinor-6-keto-PGF1alfa (PGIM) excretion in a urine sample collected in the morning before the next aspirin intake. Both biomarkers will be measured at baseline and after 14±2 days of randomized treatment

Primary

Applicable for both Part A and part B . Values were measured over 2 visits in part A and over 11 visits in part B

Part A. Based on previous findings (3, 7) we assumed a mean±SD serum TXB2 in ET patients on aspirin 100 mg od and 100 mg bid of 22±33 and 5.0±6.0 ng/ml respectively.Anticipating a 30% dropout over the entire study duration (i.e. between part A and part B, and during part B), 100 patients were planned to be enrolled in each study arm to ensure adequate statistical power.Statistical hypothesis and sample size for Part B. The same ET patients were planned to be randomized in part B of the study.

Part B v Part A

493

Pre-specified

15

2-sided

From FPFV of part A to LPLV of part B: 12/12/2017-24/10/2020

Part A: no serior adverse events recorded Part B: tthrombotic complications: 1 and 3, in the twice- and once-daily aspirin regimen, respectively; No major bleeding; clinically relevant non-major bleedings were 8 and 2 in the twice- and once-daily aspirin regimen, respectively (p=ns). Other NSAE: 97 and 84 in the od and bid arms in 20 months.

25.1

adverse events