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Patients with confirmed or suspected Covid-19 were randomly assigned to receive hydroxychloroquine with azithromycin, hydroxychloroquine alone, or usual care. The primary outcome was clinical status at 15 days, assessed on a seven-level ordinal scale. There were no significant differences between groups in the primary outcome.

Previous studies have shown that intravenous ceftriaxone or meropenem for 14 days, followed by oral trimethoprim–sulfamethoxazole for 1 year, cures 98% of people with Whipple's disease. However, intravenous therapy requires hospitalisation and carries risks for treatment-associated complications. The aim of this study was to investigate whether oral-only treatment for Whipple's disease is non-inferior to intravenous therapy. This phase 2/3, prospective, open-label, randomised, controlled, non-inferiority trial enrolled individuals aged 18 years or older with confirmed Whipple's disease from across Germany who had received treatment for less than 1 month at Charité–Universitätsmedizin Berlin. Participants were randomly assigned (1:1) with block randomisation to receive either intravenous ceftriaxone (2 g once per day) for 14 days, followed by oral trimethoprim–sulfamethoxazole (960 mg twice per day) for 12 months, or oral doxycycline (100 mg twice per day) plus hydroxychloroquine (200 mg twice per day) for 12 months. Ten participants who had already received intravenous ceftriaxone were non-randomly assigned to the intravenous treatment group. Participants in the oral-only treatment group were PCR-positive for Tropheryma whipplei in cerebrospinal fluid received trimethoprim–sulfamethoxazole (960 mg five times per day) until clearance. The primary outcome was complete clinical remission without recurrence during the observation period of 24 months, assessed in the intention-to-treat (ITT) population. The prespecified non-inferiority margin was –18%. Safety was a secondary endpoint, assessed in the ITT population. The study was registered with the EU Clinical Trials Register, EudraCT 2008–003951–54, and is completed. Between May 26, 2010, and Oct 30, 2018, we screened 310 individuals and enrolled 64 participants in the study. After exclusion of four individuals whose diagnosis was not confirmed, 31 participants were assigned to the intravenous treatment group and 29 to the oral-only treatment group. By ITT, 25 (81%) of 31 participants in the intravenous treatment group and 28 (97%) of 29 participants in the oral-only treatment group had complete clinical remission without recurrence. The risk difference was 15·9 percentage points (95% CI –1·2 to 33·1), with the lower bound of the 95% CI above our non-inferiority margin of –18%. A post-hoc per-protocol analysis confirmed the non-inferiority of oral-only treatment. No participant relapsed, but two participants in the intravenous treatment group died from nosocomial infections. Serious adverse events occurred in 13 (42%) of 31 participants in the intravenous treatment group and eight (28%) of 29 participants in the oral-only treatment group, but this difference was not statistically significant (p=0·244). Oral-only treatment of Whipple's disease was safe and non-inferior to sequential intravenous–oral treatment. Oral treatment facilitates patient management and might reduce hospital-acquired treatment complications and costs. German Research Foundation and the Robert Koch Institute. For the German translation of the abstract see Supplementary Materials section.

In this randomized, controlled trial from Europe involving patients with persistent symptoms attributed to Lyme disease, there was no benefit associated with 12 additional weeks of treatment with either doxycycline or clarithromycin–hydroxychloroquine. Patients with Lyme disease, which is caused by the Borrelia burgdorferi sensu lato complex (including B. afzelii and B. garinii in Europe), often report persistent symptoms. 1 These symptoms are also referred to as the post–Lyme disease syndrome or chronic Lyme disease and may occur after resolution of an erythema migrans rash or after other — possibly unnoticed — manifestations of early Lyme disease, regardless of whether a patient received initial appropriate antibiotic treatment. Patients present mainly with pain, fatigue, and neurologic or cognitive disturbances. 2 , 3 Previous randomized, clinical trials have not shown convincingly that prolonged antibiotic treatment has beneficial effects . . .

This was a phase I randomised comparator controlled clinical trial that assessed the pharmacokinetics (PK), and tolerability of IHL-675 A, a fixed dose combination (FDC) of cannabidiol (CBD) and hydroxychloroquine sulfate (HCQ), compared to the reference listed drugs Epidiolex (CBD) and Plaquenil (HCQ) in healthy volunteers (HVs). IHL-675 A is Incannex Healthcare Pty Ltd.’s proprietary product formulated using UniGel™ technology consisting of a solid, film coated HCQ tablet contained within a CBD-oil solution gel cap. Each IHL-675 A gel cap contains 75 mg of CBD and 100 mg HCQ. IHL-675 A is being developed for treatment of inflammatory conditions such as rheumatoid arthritis. This trial assessed the tolerability of IHL-675 A as well as pharmacokinetics of the active pharmaceutical ingredients CBD and HCQ as well as their major metabolites, compared to the reference listed drugs. The study included 3 treatment arms: IHL-675 A arm (150 mg CBD, 200 mg HCQ) and Plaquenil arm (200 mg HCQ) and Epidiolex (150 mg CBD) arm. Thirty-six participants were randomised into the 3 groups (12 per arm) and followed up for 4 weeks. Safety assessments including vital signs, electrocardiogram (ECG) parameters, and clinical laboratory parameters. Plasma concentrations of CBD, HCQ and their major metabolites, 7-OH-CBD, and 7-COOH-CBD, and desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylhydroxy-chloroquine (BDCQ) were assessed at predefined timepoints across the monitoring period and PK parameters were determined and compared between treatments using noncompartmental methods and analysis of variance (ANOVA) of log-transformed values exposure PK parameters. All adverse events were coded using the current version of the Medical Dictionary for Regulatory Activities (MeDRA) by system organ class (SOC). IHL-675 A was generally well tolerated and had a similar adverse event profile compared to Epidiolex and Plaquenil. There were no SAEs reported in this study. Both CBD and HCQ were bioavailable when dosed in IHL-675 A. There were non-statistically significant differences between the pharmacokinetics of both CBD and HCQ when compared between IHL-675 A and Epidiolex or Plaquenil. There was approximately 50% increase in C max of CBD for IHL-675 A when compared with Epidiolex, and a slight increase of approximately 10% in AUC 0−last and AUC 0−inf . The 90% CI for the ratios of AUC 0−inf , AUC 0−last and C max of CBD all extended beyond the acceptance interval of 80% – 125%. The C max of HCQ for IHL-675 A was comparable to the reference product Plaquenil, with a geometric mean squares ratio of 96.5%. There was approximately 15% decrease in AUC 0−last . The 90% CI for the ratios of AUC 0−last and C max of HCQ extended beyond the acceptance interval of 80% – 125%. The ratio of AUC 0−inf was not reliable for comparison between treatments, since the t 1/2 was estimable for only 5 of 12 participants who received IHL-675 A. IHL-675 A was generally well tolerated when delivered as an oral fixed dose with no adverse events of concern or Serious Adverse Events (SAEs). Compared to the reference listed drugs for CBD (Epidiolex 150 mg) and HCQ (Plaquenil 200 mg), there was a slightly increased exposure to CBD and its metabolites for IHL-675 A, and slightly decreased exposure to HCQ. These results support the continued clinical development of IHL-675 A. Trial Registration : ACTRN12622000289718.

Introduction Hydroxychloroquine (HCQ) is an important medication for treating systemic lupus erythematosus (SLE). Its blood concentration ([HCQ]) varies widely between patients and is a marker and predictor of SLE flares. This prospective randomised, double-blind, placebo-controlled, multicentre study sought to compare standard and adjusted HCQ dosing schedules that target [HCQ] ≥1000 ng/ml to reduce SLE flares. Patients and methods [HCQ] was measured in 573 patients with SLE (stable disease and SELENA-SLEDAI≤12) treated with HCQ for at least 6 months. Patients with [HCQ] from 100 to 750 ng/ml were randomised to one of two treatment groups: no daily dose change (group 1) or increased HCQ dose to achieve the target [HCQ] (group 2). The primary end point was the number of patients with flares during 7 months of follow-up. Results Overall, mean [HCQ] was 918±451 ng/ml. Active SLE was less prevalent in patients with higher [HCQ]. A total of 171 patients were randomised and followed for 7 months. SLE flare rates were similar in the two groups (25% in group 1 vs 27.6% in group 2; p=0.7), but a significant spontaneous increase in [HCQ] in both groups between inclusion and randomisation strongly suggested improved treatment adherence. Patients at the therapeutic target throughout follow-up tended to have fewer flares than those with low [HCQ] (20.5% vs 35.1%, p=0.12). Conclusions Although low [HCQ] is associated with higher SLE activity, adapting the HCQ dose did not reduce SLE flares over a 7-month follow-up. ClinicalTrials.gov NCT00413361

Hydroxychloroquine (HCQ) has a high variability and a long half-life in the human body. The purpose of this study was to evaluate the bioequivalence of a generic HCQ tablet (test preparation) versus a brand HCQ tablet (reference preparation) under fasting and fed conditions in a crossover design. This was an open-label, two-period randomized, single-dose, crossover study in 47 healthy Chinese subjects who were sequentially and randomly allocated either to the fed group (high-fat meal; n = 23) or the fasting group (n = 24). Participants in each group were randomized to the two arms to receive either a single 200-mg dose of the test preparation or a 200-mg dose of the reference preparation. The application of the two preparations in each patient was separated by a 28-day washout period, regarded as sufficiently long to avoid significant interference from residual drug in the body. Whole blood samples were collected over 72 hours after drug administration. A total of 23 subjects completed both the fed and the fasting parts of the trial. There were no significant differences in C , AUC , and T between the test and reference preparation (p < 0.05). Food had no significant effect on C and T (p < 0.05), but AUC values were significantly reduced under fed condition compared to fasting condition (p < 0.05). The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of C and AUC were 0.84 - 1.05 and 0.89 - 0.98 in the fed study, and 0.97 - 1.07 and 0.97 - 1.05 in the fasting study, respectively. The carryover effect due to non-zero blood concentrations resulted in higher AUC values in the second period for both test and reference formulations and had no effect on the statistical results. No serious adverse events were reported. The investigation demonstrated that the test and reference preparations are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese subjects.

Background Chronic inflammatory cardiomyopathy (infl-CMP) is a long-term sequela caused by the chronicity of acute myocarditis, especially fulminant myocarditis (FM). Hydroxychloroquine (HCQ) may benefit these patients by inhibiting the excessive inflammatory response. Methods In this multicenter, randomized trial, we evaluated the efficacy and safety of HCQ in patients with chronic infl-CMP after FM. The primary outcome of the trial was a composite of the cardiovascular outcomes of time to cardiovascular death or heart transplant, hospitalization for heart failure or recurrence of myocarditis, permanent pacemaker, or implantable cardioverter defibrillator implantation. Secondary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular internal diastolic diameter (LVIDd), plasma levels of high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and erythrocyte sedimentation rate (ESR) from baseline to 12 months. Results Fifty patients were randomized to receive HCQ combined with prednisolone (PDN) or PDN monotherapy for 12 months. Compared to PDN monotherapy, HCQ combined with PDN therapy reduced the primary composite outcome [hazard ratio (HR) = 0.28, 95% confidence interval (CI) = 0.11–0.71] and had significant changes in the increase of LVEF and the decrease of LVIDd, hs-cTnI, NT-proBNP, and hs-CRP in patients with infl-CMP. No serious drug-related adverse events were recorded in either group, indicating an acceptable safety profile. Furthermore, HCQ combined with PDN significantly reduced the levels of 16 plasma cytokines to levels comparable to healthy controls. Conclusions Twelve months of HCQ combined with PDN therapy significantly improved the prognosis and heart function, inhibited inflammation, and had acceptable safety in patients with infl-CMP after FM. Trial registration ClinicalTrials.gov identifier: NCT05961202. Graphical Abstract

Early on in the COVID-19 pandemic, we aimed to assess the effectiveness of hydroxychloroquine on reducing the need for hospital admission in patients in the community at higher risk of complications from COVID-19 syndromic illness (testing was largely unavailable at the time, hence not microbiologically confirmed SARS-CoV-2 infection), as part of the national open-label, multi-arm, prospective, adaptive platform, randomised clinical trial in community care in the United Kingdom (UK). People aged 65 and over, or aged 50 and over with comorbidities, and who had been unwell for up to 14 days with suspected COVID-19 were randomised to usual care with the addition of hydroxychloroquine, 200 mg twice a day for seven days, or usual care without hydroxychloroquine (control). Participants were recruited based on symptoms and approximately 5% had confirmed SARS-COV2 infection. The primary outcome while hydroxychloroquine was in the trial was hospital admission or death related to suspected COVID-19 infection within 28 days from randomisation. First recruitment was on April 2, 2020, and the hydroxychloroquine arm was suspended by the UK Medicines Regulator on May 22, 2020. 207 were randomised to hydroxychloroquine and 206 to usual care, and 190 and 194 contributed to the primary analysis results presented, respectively. There was no swab result available within 28 days of randomisation for 39% in both groups: 107 (54%) in the hydroxychloroquine group and 111 (55%) in the usual care group tested negative for SARS-Cov-2, and 13 (7%) and 11 (5%) tested positive. 13 participants, (seven (3·7%) in the usual care plus hydroxychloroquine and six (3.1%) in the usual care group were hospitalized (odds ratio 1·04 [95% BCI 0·36 to 3.00], probability of superiority 0·47). There was one serious adverse event, in the usual care group. More people receiving hydroxychloroquine reported nausea. We found no evidence from this treatment arm of the PRINCIPLE trial, stopped early and therefore under-powered for reasons external to the trial, that hydroxychloroquine reduced hospital admission or death in people with suspected, but mostly unconfirmed COVID-19.

In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment ‘successes’ was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment ‘successes’, molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in ‘success’ rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the ‘success’ rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.

ObjectivesTo determine the 5-year outcomes of early remission induction therapy followed by targeted treatment aimed at drug-free remission (DFR) in patients with early arthritis.MethodsIn 12 hospitals, 610 patients with early (<2 years) rheumatoid arthritis (RA) or undifferentiated arthritis (UA) started on methotrexate (MTX) 25 mg/week and prednisone (60 mg/day tapered to 7.5 mg/day). Patients not in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400 mg/day and sulfasalazine 2000 mg/day, or arm 2, switching to MTX plus adalimumab 40 mg/2 weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5 years.ResultsAfter 4 months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5 years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1 year) (220/387 (57%) remission and 135/387 (35%) SDFR in the early remission group, 50% remission, 11% SDFR in the randomisation arms without differences between the arms). More patients with UA (37% vs 23% RA, p=0.001) and more anticitrullinated protein antibody (ACPA)-negative patients (37% vs 18% ACPA-positive, p<0.001) achieved SDFR.Overall, mean Health Assessment Questionnaire was 0.6 (0.5), and median (IQR) damage progression was 0.5 (0–2.7) Sharp/van der Heijde points, with only five patients showing progression >25 points in 5 years.ConclusionsFive years of DFR-steered treatment in patients with early RA resulted in almost normal functional ability without clinically relevant joint damage across treatment groups. Patients who achieved early remission had the best clinical outcomes. There were no differences between the randomisation arms. SDFR is a realistic treatment goal.