Antibiotics and Hydroxychloroquine in Crohn's (APRiCCOT)

A Pilot Randomised Study to Compare Combination Antibiotic Therapy (Ciprofloxacin, Doxycycline and Hydroxychloroquine) With Standard Therapy (Budesonide) in the Treatment of Active Crohn's Disease

There is growing evidence that Crohn's disease may be caused by replication of bacteria, perhaps particularly E. coli, within macrophages (a specialized sort of white blood cell). Laboratory studies show that a combination of antibiotics that can penetrate macrophages (such as ciprofloxacin and doxycycline) together with the anti-malarial drug hydroxychloroquine (which makes the contents of macrophage vesicles more alkaline and helps them to kill intracellular bacteria) is particularly effective at killing the E. coli within macrophages.

Study Overview

• Status: Completed
• Conditions: Crohn's Disease
• Intervention / Treatment: Drug: Budesonide; Drug: Ciprofloxacin; Drug: Doxycycline; Drug: Hydroxychloroquine

Detailed Description

Trial Design This is an Open Label Active Study to Compare the Efficacy of 4 weeks Combination Antibiotic Therapy (Oral Ciprofloxacin 500mg bd plus Doxycycline 100mg bd and Hydroxychloroquine 200mg tds) followed by a further 20 weeks continued therapy with Doxycycline 100mg bd and Hydroxychloroquine 200mg tds with Standard Therapy (Oral Budesonide 9mg per day for 8 weeks followed by 6mg per day for 2 weeks and subsequent 3mg per day over a further 2 weeks) in the treatment of adults with Active Crohn's Disease. Patients who fail to respond by 10 weeks will be offered the opportunity to cross over onto the alternative treatment.

Primary endpoint:

• Remission, defined as Crohn's Disease activity index (CDAI) <150 at 10 weeks without addition of any other medication or treatment for the Crohn's Disease.
• Remission, defined as CDAI ≤150 maintained through to 24 weeks
• Remission, defined as CDAI ≤150 maintained through to 52 weeks

Secondary Endpoints:

• Remission defined as CDAI <150 at 4 weeks
• Response defined as a fall in CDAI by >70 points at 4 weeks and 10 weeks
• Markers of cost (days admitted to hospital, days unable to carry out normal daily activities, need for surgery)
• Quality of life at 4 weeks, at 10 weeks, or Early Withdrawal
• Patient global assessment of symptom severity by 10 cm visual analogue score at 4 weeks, at 10 weeks, or Early Withdrawal
• Adverse Events and possible drug-related side effects: nausea, diarrhoea, mood disturbance, sleep disturbance - will all be assessed at each visit

• Fall in Faecal Calprotectin

  100 patients will be randomised in order to obtain evaluable population 50 patients per treatment arm.

6.1 Informed Consent It is the responsibility of the Investigator to obtain written Informed Consent from patients before any trial procedure is carried out. All consent documentation must be in accordance with applicable regulations and GCP. Each patient is requested to sign the Patient Informed Consent Form after the patient has received and read the written patient information and received an explanation of what the study involves, including but not limited to: the objectives, potential benefits and risk, inconveniences and the subject's rights and responsibilities. A copy of the informed consent documentation (Consent Form and Subject Information) [Appendix 1] must be given to the patient. A copy will be retained in the Source Documentation and the original in the Investigator Site File.

Inclusion Criteria (i) Patient is willing to participate in the study and has signed the informed consent (ii) Patients aged 18 or over with Crohn's disease diagnosed by conventional clinical, radiological and histological criteria.

(iii) Crohn's disease involving small bowel, colon or both. (iv) Active Crohn's disease: Crohn's Disease Activity Index (CDAI)> 220 and CRP>10mg/l.

(v) Patients receiving mesalazine (5ASA) must have had a stable dose for at least one month.

(vi) Patients receiving Azathioprine, or Mercaptopurine (who will be separately stratified) must have had a stable dose for at least 3 months (vii) Women of child bearing potential must have a negative urine pregnancy test prior to the start of study medication

Exclusion Criteria (i) Patients under 18 or unable to give informed consent. (ii) Any antibiotic use within the previous 4 weeks (iii) Known sensitivity to Ciprofloxacin, Doxycycline, Hydroxychloroquine, or Budesonide (iv) Patients with a history of tendon disorders related to Fluoroquinoline administration (v) Any change to immunosuppressive therapy (Azathioprine, or Mercaptopurine) within the previous 3 months.

(vi) Use of Infliximab or Adalimumab (anti-TNF antibody) or methotrexate within the previous 3 months (vii) Concurrent use of systemic corticosteroids in excess of oral prednisolone 5 mgs/day or budesonide 3mg/day) (viii) Any change to medication for Crohn's disease in previous 4 weeks. (ix) Patients with complications requiring surgery (significant intestinal obstruction, perforation or abscess) (x) CDAI >450 (xi) Participation in other trials in the last 3 months. (xii) Serious intercurrent infection or other clinically important active disease (including renal and hepatic disease) (xiii) Pregnant, post-partum (<3months) or breast feeding females (xiv) Patients with abnormal visual acuity (that does not correct with glasses) or unexplained visual symptoms (xv) Women of Child Bearing Potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period (double barrier methods such as condoms or diaphragms with spermicidal gel or foam), and for up to 4 weeks after the study.

(xvi) Patients who need to continue to receive oral contraceptives (if unwilling to use double barrier methods), oral anticoagulants tricyclic antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, Sucralfate, or Cyclosporine

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Merseyside
    • Liverpool, Merseyside, United Kingdom, L7 8XP
      • Royal Liverpool and Broadgreen Unversity Hospitals Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient is willing to participate in the study and has signed the informed consent
• Patients aged 18 or over with Crohn's disease diagnosed by conventional clinical, radiological and histological criteria.
• Crohn's disease involving small bowel, colon or both.
• Active Crohn's disease: Crohn's Disease Activity Index (CDAI)> 220 and CRP>10mg/l.
• Patients receiving mesalazine (5ASA) must have had a stable dose for at least one month.
• Patients receiving Azathioprine, or Mercaptopurine (who will be separately stratified) must have had a stable dose for at least 3 months
• Women of child bearing potential must have a negative urine pregnancy test prior to the start of study medication

Exclusion Criteria:

• Patients under 18 or unable to give informed consent.
• Any antibiotic use within the previous 4 weeks
• Known sensitivity to Ciprofloxacin, Doxycycline, Hydroxychloroquine, or Budesonide
• Patients with a history of tendon disorders related to Fluoroquinoline administration
• Any change to immunosuppressive therapy (Azathioprine, or Mercaptopurine) within the previous 3 months.
• Use of Infliximab or Adalimumab (anti-TNF antibody) or methotrexate within the previous 3 months
• Concurrent use of systemic corticosteroids in excess of oral prednisolone 5 mgs/day or budesonide 3mg/day)
• Any change to medication for Crohn's disease in previous 4 weeks.
• Patients with complications requiring surgery (significant intestinal obstruction, perforation or abscess)
• CDAI >450
• Participation in other trials in the last 3 months.
• Serious intercurrent infection or other clinically important active disease (including renal and hepatic disease)
• Pregnant, post-partum (<3months) or breast feeding females
• Patients with abnormal visual acuity (that does not correct with glasses) or unexplained visual symptoms
• Women of Child Bearing Potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period (double barrier methods such as condoms or diaphragms with spermicidal gel or foam), and for up to 4 weeks after the study.
• Patients who need to continue to receive oral contraceptives (if unwilling to use double barrier methods), oral anticoagulants tricyclic antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, Sucralfate, or Cyclosporine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: budesonide; Oral Budesonide 9mg per day for 8 weeks followed by 6mg per day for 2 weeks and subsequent 3mg per day over a further 2 weeks	Drug: Budesonide; active comparator; Other Names: Enterocort CR
Experimental: Ciprofloxacine, doxycycline and hydroxychloroquine; Oral Ciprofloxacin 500mg bd plus Doxycycline 100mg bd and Hydroxychloroquine 200mg tds followed by a further 20 weeks continued therapy with Doxycycline 100mg bd and Hydroxychloroquine 200mg tds	Drug: Ciprofloxacin; experimental; Drug: Doxycycline; experimental; Drug: Hydroxychloroquine; oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
• Remission, defined as Crohn's Disease activity index (CDAI) <150 at 10 weeks without addition of any other medication or treatment for the Crohn's Disease.	Remission	10 weeks
• Remission, defined as CDAI ≤150 maintained through to 24 weeks	prolonged remission	24 weeks
• Remission, defined as CDAI ≤150 maintained through to 52 weeks	prolonged remission	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
• Remission defined as CDAI <150 at 4 weeks	remission	4 weeks
• Response defined as a fall in CDAI by >70 points at 4 weeks and 10 weeks	response	4 weeks and 10 weeks
• Markers of cost (days admitted to hospital, days unable to carry out normal daily activities, need for surgery)	cost effectiveness	52 weeks
• Quality of life at 4 weeks, at 10 weeks, or Early Withdrawal	Quality of life	4 weeks and 10 weeks
• Patient global assessment of symptom severity by 10 cm visual analogue score at 4 weeks, at 10 weeks, or Early Withdrawal	efficacy	4 weeks and 10 weeks
• Adverse Events and possible drug-related side effects: nausea, diarrhoea, mood disturbance, sleep disturbance - will all be assessed at each visit	adverse event monitoring	throughout 12 month follow-up
• Fall in Faecal Calprotectin	efficacy	4 weeks, 10 weeks, 24 weeks, 52 weeks

Collaborators and Investigators

• Sponsor: Royal Liverpool University Hospital
• Collaborators: National Institute for Health Research, United Kingdom; National Association for Colitis and Crohn's Disease

Publications and helpful links

General Publications

• Rhodes JM, Subramanian S, Flanagan PK, Horgan GW, Martin K, Mansfield J, Parkes M, Hart A, Dallal H, Iqbal T, Butterworth J, Culshaw K, Probert C. Randomized Trial of Ciprofloxacin Doxycycline and Hydroxychloroquine Versus Budesonide in Active Crohn's Disease. Dig Dis Sci. 2021 Aug;66(8):2700-2711. doi: 10.1007/s10620-020-06477-y. Epub 2020 Jul 17.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2014
• Primary Completion (Actual): April 18, 2019
• Study Completion (Actual): September 30, 2019

Study Registration Dates

• First Submitted: January 31, 2013
• First Submitted That Met QC Criteria: January 31, 2013
• First Posted (Estimate): February 4, 2013

Study Record Updates

• Last Update Posted (Actual): October 31, 2019
• Last Update Submitted That Met QC Criteria: October 29, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: hydroxychloroquine; antibiotics; doxycycline; Crohn's; ciprofloxacin
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Cytochrome P-450 CYP1A2 Inhibitors; Budesonide; Doxycycline; Ciprofloxacin; Hydroxychloroquine
• Other Study ID Numbers: Royal_Liverpool; 2008-001137-99 (EudraCT Number)