Le Kremlin Bicetre

1.0 Hypothesis for the study Antibiotic therapies currently recommended for the treatment of acute pyelonephritis (AP) in children, whether fully by the oral route or initially intravenous (IV, 3 days) followed by the oral route, have a duration of 7 to 14 days (10 days in France). In children with no prior urological malformation, the global clinical and microbiological cure rate after antibiotic treatment completion is around 95%. Recurrence occurs in less than 5% of cases in the 3 months following AP. Renal scarring, when documented, concerns 15% of children 6 months after treatment. Renal scarring can be associated with chronic renal disease. The investigators hypothesize that 3 days of IV treatment is equivalent to extending to 10 days with an oral therapy to prevent long-term renal scarring. The investigators also hypothesize that while achieving equivalent clinical and microbiological success, and prevention of re-infections in the following 3 months, 3 days of IV treatment reduces the risk of acquisition of resistant strains of Enterobacteriaceae and increases the gut microbotia diversity compared to extending to 10 days with an oral therapy. 2.0 Description of knowledge relating to the condition in question Acute pyelonephritis (AP) is the most common proven bacterial infection in pediatric clinical practice. It can lead to sepsis or renal abscess and induce long-term complications such as renal scarring. Renal scarring during childhood can lead to hypertension or chronic renal disease at adult age, although the link between AP and chronic renal disease has not been firmly established. AP is most frequently due to Enterobacteriaceae, mainly Escherichia coli. Extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) now account for 5% of AP in France and represent a serious threat to public health, owing to limited therapeutic options. The overall clinical success rate in children treated for AP is around 95% and is not significantly different when ESBL-E are implicated. In children with no prior urological malformation, recurrence in the following 3 months occurs in less than 5% of cases. Antibiotic treatment decreases the risk of renal scarring, which remains important, around 15% (95% CI: 11-18) in the largest meta-analysis. Moreover, delay in treatment of AP is associated with permanent renal scarring. In children without prior urological malformation, acute complications are exceptional, even in the presence of bacteraemia. Short courses of intravenous (IV) antibiotics (2-4 days) followed by oral therapy have proved to be as efficient as longer courses (7-14 days) of IV treatment. For children aged ≥ 1 month, oral treatment alone for 10 to 14 days has proved non inferior to initial IV antibiotics (2-4 days) followed by oral therapy (total 10 to 14 days). French Paediatric guidelines recommend a short course (up to 4 days) of IV amikacin and/or ceftriaxone followed by oral therapy (total 10 days), with the possibility, for children aged \> 3 months of a 10-day course of oral cefixime \[12\]. In children initially treated IV, the oral relay occurs once the urine culture and antibiogram are available. The American Association of Pediatrics that focused on children aged 2 to 24 months recommends either an oral or a sequential IV/oral treatment for a total of 7 to 14 days, while the British NICE guidelines recommend an exclusively oral route only for children aged ≥ 3 months In practice, most centers initiate an IV treatment in a large subset of patients (ongoing practice analysis on the management of AP in children in France, personal data, to be published in 2021). An initial IV treatment is particularly used in young children, with an age cut-off varying between 3 months and 3 years according to the center. It is also used to secure the absorption of the treatment if the child vomits, is unable to take oral antibiotics or is severely unwell. The excellent short-term and the good long-term clinical outcomes in children treated for AP questions the need for a 10-day course of antibiotics. In adults, shorter treatments, such as amikacin for 5 days, have been validated for the treatment of uncomplicated AP. Recently published studies (Zaoutis 2023, Montini 2024) have compared a 5-day oral treatment vs 10-day oral treatment for AP in children. However, the first study (Zaoutis 2023) mainly included (63%) children with a non-febrile urinary tract infection (ie not an AP). The second only included children aged \> 3 month. A practice survey conducted prior to our protocol had shown that many departments were already reluctant to treat infants under 1 year old, and particularly those under 3 months old, by oral route, warranting clinical trials including children \< 3 month old. Third-generation cephalosporins (3GC), such as ceftriaxone, rapidly reduce the richness and diversity of the gut microbiota and also select subpopulations of resistant bacteria, particularly by acquisition of extended spectrum beta-lactamases, a major public health issue. There is no data on the impact of antibiotic relays on the gut microbiota. Since each antibiotic has its own anti-bacterial spectrum, a sequence of treatments could have an additive or even synergistic deleterious effect on the gut microbiota. This may in particular be the case in children treated with IV ceftriaxone for 3 days followed by cotrimoxazole for 7 days, as recommended in France in first intention. 3.0 Summary of relevant pre-clinical experiments and clinical trials 1999 Hoberman et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children This was a non-inferiority study between oral cefixime for 14 days and intravenous ceftriaxone for 3 days followed by oral cefixime for 11 days. One of the outcomes was the occurrence of renal scarring. It included children aged 1 to 24 months. A total of 306 children were included. Renal scarring at 6 months was noted in 9.8% children treated orally versus 7.2% of children treated intravenously. The study conclude that oral treatment was safe. The main limit of the study was the lower rate of renal scar in both arms compared to other studies, probably linked to a female/male sex ratio of 9:1 (with a median age of 8 months), when the sex ratio is in favour of boys before 1-year-old. 2007, Montini et al. Antibiotic treatment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial This was a multicentre, randomised controlled, open labelled, parallel group, non-inferiority trial comparing oral co-amoxiclav for 10 days to parenteral ceftriaxone for three days, followed by oral co-amoxiclav for 7 days. Primary outcome was the rate of renal scarring after 12 months. A total of 502 children aged 1 month to \<7 years with clinical pyelonephritis were included. Intention to treat analysis showed no significant differences between oral (n=244) and parenteral (n=258) treatment, both in the primary outcome (scarring scintigraphy at 12 months 27/197 (13.7%) v 36/203 (17.7%), and secondary outcomes: time to defervescence, white cell count at day 3, and percentage with sterile urine at day 3 (99.5% n both arms). The results were similar in the subgroups of children older and younger than 2 years (data not shown in the paper). 2012, Boquet et al. Randomized trial of oral versus sequential IV/oral antibiotic for acute pyelonephritis in children PHRC AOM 04 105; NCT00136656 This was a non-inferiority study between oral cefixime for 10 days and IV ceftriaxone for 4 days followed by oral cefixime for 6 days on the occurrence of renal scarring. It included children aged 1 to 36 mont with a first proven urinary tract infection and procalcitonin concentration ≥ 0.5 ng/mL s. The primary endpoint was the proportion of renal scar measured by 99mTc-DMSA renal scintigraphy 6 to 8 months after treatment. The study included a total 171 children of the 698 expected. The incidence of renal scarring was 30.8% in the oral treatment group and 27.3% for children who received the sequential treatment. The trial could not demonstrate statistically the non-inferiority due to insufficient enrolment. 2023, Zaoutis et al. Short-Course Therapy for Urinary Tract Infections in Children: The SCOUT Randomized Clinical Trial PMID: 37358858 ; NCT01595529, This was a randomized clinical noninferiority trial at 2 children's hospitals. Participants included children aged 2 months to 10 years with UTI exhibiting clinical improvement after 5 days of antimicrobials. The study compared another 5 days of antimicrobials (standard-course therapy) or 5 days of placebo (short-course therapy). The primary outcome, treatment failure, was defined as symptomatic UTI at or before the first follow-up visit (day 11 to 14 A total of 664 children were randomized (639 female \[96%\]; median age, 4 years): 2 of 328 assigned to standard-course (0.6%) and 14 of 336 assigned to short-course (4.2%) had a treatment failure. There were no differences between groups in rates of UTI after the first follow-up visit, incidence of adverse events, or incidence of gastrointestinal colonization with resistant organisms. 2024, Montini et al. Short Oral Antibiotic Therapy for Pediatric febrile Urinary Tract Infections: A Randomized Trial. \[25\] PMID: 38146260 This was a multicenter, investigator-initiated, parallel-group, randomized, controlled trial. We randomly assigned children aged 3 months to 5 years with a noncomplicated fUTI to receive amoxicillin-clavulanate for 5 or 10 days. The primary end point was the recurrence of a urinary tract infection within 30 days after the completion of therapy. Secondary end points were the difference in prevalence of clinical recovery, adverse drug-related events, and resistance to amoxicillin-clavulanic acid and/or to other antibiotics when a recurrent infection occurred. The study included a total of,175 children and 142 underwent randomization. The recurrence rate of UTI within 30 days of the end of therapy was 2.8% (2/72) in the short group and 14.3% (10/70) in the standard group. The recurrence rate of fUTI within 30 days from the end of therapy was 1.4% (1/72) in the short group and 5.7% (4/70) in the standard group.

This is a Phase 2, randomized, multicenter, basket study of vosoritide in children with Turner syndrome, short stature homeobox-containing gene (SHOX) deficiency, or Noonan syndrome who have inadequate growth during or after human growth hormone (hGH) treatment. The study is intended to characterize the short-term efficacy and safety of 3 dosing regimens of vosoritide. The efficacy and safety of the vosoritide therapeutic dose will be further evaluated, and an analysis of the impact of vosoritide on final adult height (FAH).

LTFU PAH sotatercept study MK-7962-004 (Obsolete Identifier: NCT04796337) has been incorporated into the current MK-7962-038 (NCT07218029) study for administrative reasons. The MK-7962-004 study is no longer enrolling participants and will be formally closed. Only those who participated in MK-7962-004 may be eligible to continue into MK-7962-038.

Study 8123-001 is a Phase 1/2, multicenter, open-label, dose-escalation study to assess the safety, tolerability, PK and PD of KK8123, with an optional safety extension period. This study is comprised of a Screening Period followed by Part 1 and Part 2. The Screening Period will last up to 28 days (including obtaining informed consent). Part 1 is a Dose Escalation Period consisting of a nominal (planned) Treatment Period (all cohorts) and Observation Period of 32 to 44 weeks, and Part 2 is an optional Extension Period.

This study is open to people with idiopathic pulmonary fibrosis (IPF) or progressive pulmonary fibrosis (PPF). They can only take part if they have completed treatment in a previous study with a medicine called nerandomilast or BI 1015550. The goal of this study is to find out how well people with pulmonary fibrosis tolerate long- term treatment with nerandomilast. The study also tests whether nerandomilast improves lung function and prolongs the time until symptoms get worse, participants need to go to the hospital, or die. Every participant takes nerandomilast as tablets for up to 1 year and 10 months. The participants may also continue their regular treatment for pulmonary fibrosis during the study. Participants visit their doctors regularly. During these visits, the doctors collect information on any health problems of the participants. Participants also regularly do lung function tests.

The main objective is to assess the safety and tolerability of inebilizumab in adult participants with active and refractory systemic lupus erythematosus (SLE) with nephritis (Subprotocol A) and to assess the safety and tolerability of subcutaneous (SC) blinatumomab in adult participants with active and refractory SLE with and without nephritis (Subprotocol B Part A) and in adult participants with active refractory rheumatoid arthritis (RA) (Subprotocol C Part A). The trial will also assess the efficacy of SC blinatumomab in adult participants with active and refractory SLE with and without nephritis (Subprotocol B Part B and Subprotocol C Part B).

Following a minimum 6 month observational period in which baseline growth is assessed, participants in the vosoritide and placebo groups will complete a minimum of 6 months of randomized treatment (maximum of 6 months of placebo treatment), followed by open-label treatment with vosoritide until they reach near-final adult height, or at least 16 years of age for females or 18 years of age for males, whichever comes later. Participants randomized to the hGH group will receive open-label hGH for a minimum of 4 years.

The study is a phase II trial designed to evaluate the clinical efficacy, safety, and tolerability of MAS825 in pediatric and adult participants with Still's disease

This is a randomized, double-blind, placebo-controlled clinical study to evaluate the safety and efficacy of 2 doses of AP01 (pirfenidone solution for inhalation) versus placebo on top of standard of care in participants with PPF over 52 weeks. Up to 300 eligible participants will be randomized to 1 of 3 treatment arms: AP01 high dose, AP01 low dose, or placebo.

This Phase 2/3 plus open-label extension study is designed to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of atumelnant treatment in pediatric participants with classic CAH. Part A is a Phase 2, open-label, semi-sequential cohorts portion of the study. Part B is the Phase 3, double-blind, randomized, placebo controlled confirmatory portion of the study. Part C is the open-label extension (OLE) portion of the study. Participants in Part A and B are eligible to enroll in Part C (OLE). A total of approximately 153 participants may be enrolled in the study (planned and optional cohorts) ages 1 to \< 18 years old. The first 3 cohorts in Part A are for ages 12 to \<18 years and will be sequential, and Safety Review Committee (SRC) review of data and approval to proceed is required prior to enrolling each subsequent cohort. The fourth cohort in Part A is for ages 1 to 11 years old and will begin after Cohorts 1 and 2 have been completed, additional requirements are fulfilled, and following SRC review of Cohorts 1 and 2 data.