The HIt HArd and hiT Early in Multiple Sclerosis Trial (HiHat)

The HIt HArd and hiT Early in Multiple Sclerosis Trial - HiHat Trial A Phase 2 Study of Sequential Treatment With Rituximab and Cladribine for Relapsing-remitting Multiple Sclerosis

The HiHat trial is a Phase 2 study aimed at evaluating the safety and feasibility of sequential treatment with rituximab and cladribine in patients with relapsing-remitting multiple sclerosis (RRMS). The study follows a prospective, open-label, single-arm design, with 60 RRMS patients receiving both treatments in a controlled regimen: two cycles of rituximab (1,000 mg each, biweekly) followed by two cycles of cladribine (30 mg per cycle for three days per cycle) spaced one month apart. Participants are monitored over 24 months through clinical assessments, MRI, and biomarker analyses. The primary objective is to evaluate whether the rate of serious adverse events (SAE) is acceptably low. Secondary objectives include assessing impacts on MRI lesion count, relapse rates, disability progression, quality of life, and safety.

Study Overview

• Status: Not yet recruiting
• Conditions: Relapsing-remitting Multiple Sclerosis
• Intervention / Treatment: Drug: Sequential treatment with rituximab and cladribine

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Joachim Burman, MD, PhD; Phone Number: +46 18 611 50 88; Email: joachim.burman@uu.se

Study Locations

• Sweden
  • Falun, Sweden, 79182
    • Falu Lasarett, Neurologen
    • Contact: Martin Othozon, MD; Phone Number: +46 23 490000; Email: martin.othozon@regiondalarna.se
  • Gävle, Sweden, 80324
    • Gävle sjukhus, Neurologmottagningen
    • Contact: Sara Moussavi, MD; Phone Number: +46 26 15 43 44; Email: kliniskaprovningar@regiongavleborg.se
  • Karlstad, Sweden, 651 85
    • Centralsjukhuset Karlstad, Neurologi och Rehabiliteringskliniken
    • Contact: Oskar Wickberg, MD; Phone Number: +46 10 8315000; Email: oskar.wickberg@regionvarmland.se
  • Uppsala, Sweden, 75185
    • Uppsala University Hospital
    • Contact: Joachim Burman, MD, PhD; Phone Number: +46 18 611 5088; Email: joachim.burman@uu.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of RRMS according to the 2017 revised McDonald criteria,
• With disease activity within the preceding year in the form of: a clinical relapse, and/or evidence of ≥2 T2 lesions on MRI scan, and or presence of gadolinium enhancing lesions on an MRI scan,
• Age 18 - 50 years (inclusive) of age,
• Disease duration ≤10 years (since MS diagnosis),
• EDSS 0 - 5.5 (inclusive),
• Signed informed consent.

Exclusion Criteria:

• Diagnosis of progressive MS,
• Previous use of rituximab (or any other B-cell depleting monoclonal antibody) and/or cladribine,
• Pregnant or lactating women,
• Unwilling to use contraception during the treatment period and the first year after completing the treatment course,
• Patients having contraindication for or otherwise not compliant with MRI investigations,
• Simultaneous treatment with other immunosuppressive drugs,
• Infection with human immunodeficiency virus (HIV),
• Active, severe infections (e.g. hepatitis or tuberculosis),
• Severe cardiac disorder,
• Moderate or severe renal impairment (eGFR <60).
• Active malignancy,
• No prior exposure to varicella virus,
• Vaccination within 4 weeks of first dose of study medication,
• Severe psychiatric condition.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients with relapsing-remitting multiple sclerosis (RRMS); The study population will consist of subjects with RRMS with less than 10 years disease duration.	Drug: Sequential treatment with rituximab and cladribine; Two cycles of rituximab (1,000 mg each, biweekly) followed by two cycles of cladribine (30 mg per cycle for three days per cycle) spaced one month apart.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-related Serious Adverse Events	The primary objective of the study is to evaluate whether the SAE rate associated with sequential treatment of rituximab followed by cladribine is acceptably low. The proportion of patients with at least one treatment-related SAE (relationship ≥ possible) will be reported.	From start of treatment until end of follow-up at 2 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Magnetic Resonance Imaging (MRI) lesions	Proportion of patients with a new MRI lesion will be reported.	The first scan made after the treatment course has been completed (week 12) will be compared with the scan at 2 years to determine if new lesions have occurred.
Relapses	The proportion of patients with at least one confirmed clinical relapse will be reported.	From start of treatment until the end of follow-up at 2 years.
Disability	The proportion of patients with confirmed disability worsening, rated with the Kurtzke Expanded Disability Status Scale (EDSS, ranges from 0 to 10).	EDSS at baseline will be compared with EDSS at end of follow-up at 2 years.
Symbol Digit Modalities Test (SDMT)	The proportion of patients with worsened, unchanged, or improved SDMT (score range 0-110, higher numbers are better) will be reported. A change by at least 4 points on the SDMT will be considered a clinically meaningful change.	SDMT at baseline is compared with SDMT at end of follow-up at 2 years.
Quality of life (physical) measured by MSIS-29 (Multiple Sclerosis Impact Scale)	The proportion of patients with improvement in MSIS-29 physical (rated 0-100, higher is worse) will be reported. A change by 8 points in the physical domain will be considered a clinically meaningful change.	Baseline compared with end of follow-up at 2 years.
Quality of life (MSIS-29 psychological)	The proportion of patients with improvement in MSIS-29 psychological (rated 0-100, higher is worse) will be reported. A change by 6 points in the psychological domain will be considered a clinically meaningful change.	Baseline compared with end of follow-up at 2 years.
Treatment-related Adverse Events	The proportion of patients with treatment-related adverse events of mild or moderate severity (relationship ≥ probable) to the study medication.	From start of treatment to end of follow-up at 2 years.

Collaborators and Investigators

• Sponsor: Uppsala University

Study record dates

Study Major Dates

• Study Start (Estimated): April 15, 2026
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: November 21, 2025
• First Submitted That Met QC Criteria: April 1, 2026
• First Posted (Actual): April 8, 2026

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 1, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: rituximab; cladribine
• Additional Relevant MeSH Terms: Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Purines; Nucleosides; Ribonucleosides; Antibodies, Monoclonal, Murine-Derived; Deoxyribonucleosides; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Deoxyadenosines; Rituximab; Cladribine
• Other Study ID Numbers: HiHat; 2024-519700-28-01 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No